Histamine or prostaglandin (PG) E1 or E2 administered to rabbits topically alone in high doses produced conjunctival vasodilation associated with little or no edema while their mixture at lower concentrations produced conjunctival vasodilation associated with profound edema. Sections of tissues treated with the mixture of histamine and PGE1 or PGE2 showed widespread epithelial and subepithelial inflammatory cellular infiltration. Conjunctival smears from eyes treated with the histamine/PG mixture contained small lymphocytes and polymorphonuclear leukocytes, including eosinophilic and occasionally basophilic cells. Differential staining of the polymorphs demonstrated both eosinophils and pseudoeosinophils. Histological examination of the conjunctival smears and sections of the lids obtained from eyes treated with either histamine or PGE1 or PGE2 alone did not show any detectable increase of inflammatory cells when compared to normal controls. The clinical and histological results indicate that the synergistic effect of histamine with PGs of the E-type in the conjunctiva produces an inflammatory response similar to that seen in various clinical forms of human allergic conjunctivitis. Such a response could not be produced by histamine or PGE1 or PGE2 alone even at much higher doses than in the mixture. The data indicate that an interplay of several different mediators may be crucial in the conjunctival response in allergy.