A mouse model of conjunctivitis has been developed by topical application of compound 48/80 (C48/80), an agent that triggers mast cell degranulation. We examined the responsiveness of C57BL/6, C3H/HeN, and ASW/J mouse strains to C48/80 stimulation, and of a mutant strain with mast cell depletion (WBB6F1/J and its sham control). Conjunctivae were collected and examined histopathologically at 15 min and 1,6,24,48 and 72 h after topical C48/80 administration. Conjunctival inflammation developed in all strains, although the severity varied. The conjunctivitis was characterized clinically by irritation, discharge, erythema, and chemosis. Pathology showed conjunctival infiltration with neutrophils, macrophages, CD4+ T lymphocytes, and a few eosinophils. Degranulation of mast cells and evacuation of goblet cells were also observed. Late-phase inflammatory reactions peaked 6-24 h after C48/80 administration and resolved by 48-72 h. WBB6F1/J mice had much less inflammation than their sham controls. In conclusion, topical C48/80 induced a conjunctival inflammatory response similar to allergen-induced conjunctivitis. The depletion of mast cells significantly reduced the inflammation. This model which consistently mimics the clinical signs and histopathological processes of allergic conjunctivitis in humans, is practical and reliable for the evaluation of new anti-allergic medications and for the investigation of conjunctival cellular responses in the allergic inflammatory cascade.