To evaluate antiallergic agents, we conducted five allergen challenge studies of increasing refinement. The final study design that evolved included two baseline visits, when skin test-positive subjects were administered a bilateral ocular allergen challenge. At the first visit, the threshold dose of reactivity was determined by increasing allergen doses at 10-minute intervals. At the second baseline visit, 3 days later, the responsive subjects were challenged with the final, highest dose used on visit 1 to assure that the allergic reaction was reproducible and not a cumulative effect of multiple allergen doses. The responsive subjects then returned 3 days later for the drug efficacy evaluation. After a slit-lamp examination, subjects were pretreated with the test drug in one eye and the placebo in the fellow eye in a randomized, double-masked fashion. After 10 minutes, subjects were challenged bilaterally with the allergen dose identified on the previous visits. Postchallenge evaluations of hyperemia, itching, chemosis, eyelid swelling, and tearing were performed at 3, 10, and 20 minutes. Subjects were rechallenged 4 hours after drug administration to assess duration of action. Slit-lamp examinations were again performed at the same intervals as after the initial challenge. A total of 396 subjects were given a baseline allergen challenge; 83.6% responded with a moderate (2+) ocular allergic reaction. Of the 266 given a second baseline challenge, 87.2% responded positively again, suggesting that ocular challenge was highly correlated with skin reactivity and reproducible with a second challenge. No statistically significant difference in redness and itching was found when both eyes were challenged with the same dose of allergen.(ABSTRACT TRUNCATED AT 250 WORDS)