During July and August of 1980, a case/control study was conducted in St. Louis and Kansas City, Missouri, in an effort to gain insight into risk factors associated with heatstroke. A total of 208 cases of heatstroke were identified from hospital records; 156 cases (73 fatal) were used for the study. Questionnaires were used to obtain data on the heatstroke victims, and on 462 comparison subjects, matched by neighborhood, age, and sex. A family member or close friend served as respondent for fatal cases. Potential risk factors were divided into three categories: environmental, social and behavioral, and biological and medical. Increased risk was associated with alcoholism, having living quarters on the higher floors of multistory dwellings, and using potent tranquilizers including phenothiazines, butyrophenones, or thioxanthenes. The use of home air conditioning units, spending more overall time in air conditioned places, and living in a residence well shaded by trees and shrubs, were factors associated with low incidence of heatstroke. Decreased risk was also associated with having the ability to take care of oneself, being accustomed to vigorous physical activity, but reducing such activity during the heat, and ingesting extra liquids. The authors suggest that effective preventive measures should start with those unable to care for themselves. Patients who are taking antipsychotic drugs should be advised of their increased risk due to the ingestion of these medications.