Although the prevalence of IgE-mediated latex allergy has increased over the past decade, the circumstances that culminate in sensitization remain uncertain. The objective of these studies was to evaluate the role which sensitization route plays in the development of latex allergy using murine models representative of potential exposure routes by which health care workers (topical and respiratory) and spina bifida patients (subcutaneous) may be sensitized. BALB/c mice administered latex proteins by the subcutaneous, topical, intranasal or intratracheal routes exhibited dose responsive elevations in total IgE. Subcutaneous and intratracheal exposures resulted in comparable IgE levels > 8,000nglml) 30 days after initial protein administration. Topical applications induced IgE production (approximately 6,000ng/ml) in abraded and non-tape stripped mice following daily exposures for 7 weeks. Intranasal instillation resulted in the lowest total IgE concentrations (<1,500ng/ml). Active Cutaneous Anaphylaxis and in vitro splenocyte stimulation initially demonstrated specificity of the murine immune response to latex proteins in subcutaneously sensitized mice. Subsequently, immunoblot analysis was used to compare latex-specific IgE production amongst sensitization routes. Immunoblots of IgE from subcutaneously sensitized mice demonstrated recognition of latex proteins with molecular weights near 14 kDa and 27 kDa. These protein sizes are consistent with the molecular weights of major latex allergens (hev b 1 and hev b 3) to which high percentages of spina bifida patients develop antibodies. The 27 kDa latex protein was not evident following blotting of sera from mice sensitized by any other route. Mice sensitized by intratracheal or topical administration exhibited combined IgE recognition of latex proteins near 14 kDa, 35 kDa and 92 kDa; these molecular weights are similar to other latex allergens (hev b 6, hev b 2 and hev b 4) commonly recognized by IgE of health care workers. Sera from intratracheally sensitized mice demonstrated unique recognition of the 92 kDa latex protein. Mice sensitized to latex proteins by topical, intranasal, or intratracheal exposures exhibited bronchoconstriction (increased PENH) as measured by whole body plethysmography following respiratory challenge with latex proteins; subcutaneously sensitized mice were unresponsive. These differences in latex specific IgE immunoblot profiles, and the altered pulmonary responses, amongst the four different sensitization routes suggest that exposure routes leading to sensitization may play a role in determining the primary allergen(s) and the clinical manifestation of the allergic responses in latex allergy.