Monkeypox Case Definitions

Suspect case

• New characteristic rash* OR
• Meets one of the epidemiologic criteria and has a high clinical suspicion for monkeypox

Probable case

• No suspicion of other recent Orthopoxvirus exposure (e.g., Vaccinia virus in ACAM2000 vaccination) AND demonstration of the presence of
  • Orthopoxvirus DNA by polymerase chain reaction of a clinical specimen OR
  • Orthopoxvirus using immunohistochemical or electron microscopy testing methods OR
  • Demonstration of detectable levels of anti-orthopoxvirus IgM antibody during the period of 4 to 56 days after rash onset

Confirmed case

Demonstration of the presence of monkeypox virus (MPXV) DNA by polymerase chain reaction testing or Next-Generation sequencing of a clinical specimen

OR

Isolation of MPXV in culture from a clinical specimen

Epidemiologic criteria

Within 21 days of illness onset:

• Reports having contact with a person or people with a similar appearing rash or who received a diagnosis of confirmed or probable monkeypox OR
• Had close or intimate in-person contact with individuals in a social network experiencing monkeypox activity, this includes men who have sex with men (MSM) who meet partners through an online website, digital application ("app"), or social event (e.g., a bar or party) OR
• Traveled outside the US to a country with confirmed cases of monkeypox or where MPXV is endemic OR
• Had contact with a dead or live wild animal or exotic pet that is an African endemic species or used a product derived from such animals (e.g., game meat, creams, lotions, powders, etc.)

Exclusion criteria

A case may be excluded as a suspect, probable, or confirmed case if:

• An alternative diagnosis can fully explain the illness OR
• An individual with symptoms consistent with monkeypox does not develop a rash within 5 days of illness onset OR
• A case where high-quality specimens do not demonstrate the presence of orthopoxvirus, MPXV, OR antibodies to orthopoxvirus

Interim case definitions for clade I monkeypox*

As of December 12, 2025

Suspect case, clade I

• Probable or confirmed monkeypox as defined above AND
• At least one of the Clade I Epidemiologic Criteria (below)

Probable case, clade I

• Probable or confirmed monkeypox as defined above AND
• At least one of the Clade I Epidemiologic Criteria (below) AND
• Clade II MPXV-negative by polymerase chain reaction testing without Next-Generation sequencing of a clinical specimen to confirm clade

Confirmed case, clade I

• Demonstration of the presence of clade I MPXV DNA by polymerase chain reaction testing OR Next-Generation sequencing of a clinical specimen

Clade I epidemiologic criteria

Within 21 days of illness onset:

• Traveled to an area with evidence of sustained human to human transmission of clade I monkeypox or where clade I MPXV is endemic, OR
• Reports having contact with person with confirmed, probable or suspect clade I monkeypox, OR
• Had close or intimate in-person contact with individuals in a social network currently experiencing clade I monkeypox activity, OR
• Had contact with a dead or live wild animal or exotic pet that is a central African endemic species or used a product derived from such animals (e.g., game meat, creams, lotions, powders, etc.)

*This interim definition applies to the current situation with clade I cases globally. If the situation changes, this interim definition will be updated accordingly.

Monkeypox virus reinfection

MPXV reinfection occurs when a person who was classified as a confirmed or probable monkeypox case has a recurrence of monkeypox symptoms after complete resolution† of the initial confirmed or probable infection.

Suspect monkeypox reinfection

Meets the clinical description of MPXV reinfection and any of the following criteria:

• New rash* OR
• Meets one of the epidemiologic criteria and has a high clinical suspicion for monkeypox

Probable monkeypox reinfection

Meets the criteria for a suspect MPXV reinfection case AND demonstrates one of the following from a patient specimen:

• Orthopoxvirus or MPXV DNA by polymerase chain reaction of a clinical specimen OR
• Orthopoxvirus using immunohistochemical or electron microscopy testing methods OR
• Demonstrable increase in anti-Orthopoxvirus IgG antibodies in paired serum samples collected within 3 days of symptom onset and 7-14 days after symptom onset, for patients with no prior monkeypox/smallpox vaccination or vaccinated ≥180 days prior to symptom onset

Confirmed monkeypox reinfection

• Meets criteria for probable MPXV reinfection case AND
• Has significant single nucleotide polymorphisms (SNPs) or genetic variation between MPXV genetic sequences‡ from clinical specimens obtained from 2 or more episodes of MPXV infection separated by complete resolution of symptoms within the same individual

Considerations for monkeypox reinfection

• Patients with severe immunodeficiency (e.g., people living with HIV with CD4 counts <200) can be at risk for persistent and/or relapsed MPXV infections.
• Persistent MPXV infection occurs when there is no clinical improvement or resolution of initial symptoms.
• Relapsed MPXV infection occurs when MPXV infection has improved but has not completely resolved, followed by clinical worsening or new monkeypox symptoms.
  
• Patients may develop symptoms caused by other infections during MPXV infection or after their initial infection resolves.

*The characteristic rash associated with monkeypox lesions involve deep-seated and well-circumscribed lesions, often with central umbilication, and lesion progression through specific sequential stages: macules, papules, vesicles, pustules, and scabs. Monkeypox lesions can sometimes be confused with other diseases that are more commonly encountered in clinical practice (e.g., secondary syphilis, herpes, and varicella zoster). Historically, accounts of patients co-infected with MPXV and other infectious agents (e.g., varicella zoster, syphilis) have been reported, so patients with a characteristic rash should be considered for MPXV testing, even if tests are positive for other infections. People with severe immunodeficiency (e.g., advanced HIV) may have skin lesions that are necrotic, diffuse, and plaque-like.

† Complete resolution is defined as disappearance of all clinical symptoms of monkeypox including fever, chills, lymphadenopathy, skin rashes, lesions, or other skin disturbances caused by MPXV, and any other persistent symptoms associated with MPXV infection.

‡ If there are no substantial single nucleotide polymorphisms (SNPs) or significant genetic variation between MPXV sequences from clinical specimens from two or more episodes of MPXV infection obtained from the same individual then the case should be classified as a probable case.