PURPOSE: To evaluate the efficacy and safety of loteprednol etabonate 0.5% as prophylactic treatment for the ocular signs and symptoms of seasonal allergic conjunctivitis. METHODS: In this randomized, double-masked, placebo-controlled, parallel study, 293 adults with history of seasonal allergic conjunctivitis were treated with either loteprednol etabonate or vehicle (placebo) four times daily, beginning before the onset of the allergy season and continuing for 6 weeks. The primary efficacy measure was a primary composite score (sum of itching and bulbar conjunctival injection scores). Supportive efficacy measures were the investigator global assessment and a secondary composite score (sum of tearing, erythema, chemosis, and discomfort scores), all calculated during the 21-day peak pollen season. RESULTS: The proportion of patients who never developed moderate or severe signs and symptoms of allergy during the peak pollen season in the loteprednol etabonate treatment group was greater than that in the placebo group. For the primary composite score, this efficacy criterion was reached by 94% of patients (136/145) in the loteprednol etabonate group and 78% of patients (111/143) in the placebo group (P = .001). The magnitude of effect was similar for the investigator global assessment (86% [118/138] vs 64% [87/137]; P < .001) and, although not statistically significant, the secondary composite score (77% [112/145] vs 68% [97/143]; P = .092). None of the loteprednol etabonate-treated patients had an intraocular pressure increase of 10 mm Hg or more, whereas two placebo patients did. CONCLUSIONS: Loteprednol etabonate is generally effective in prophylaxis of seasonal allergic conjunctivitis and has an acceptable safety profile.