In order to compare the relative efficacy of topical antihistamines with balanced saline solution (BSS) and benzalkonium chloride (BC) in the early phase of allergic conjunctivitis in an animal model of ocular anaphylaxis, 96 male guinea pigs were sensitized with intraperitoneal egg albumin (EA) and aluminum hydroxide. Seventy-six animals were used for determination of Evans blue (EB) extravasation and 20 for clinical evaluation of the allergic response (redness, edema, discharge and itch-scratch response). Eighteen days after sensitization the animals were topically challenged by conjunctival instillation of EA and treated 15 min before and 15 min after challenge with commercially available drugs (ketotifen, ketotifen single dose units [SDU], olopatadine, azelastine, spaglumic acid and emedastine) and controls (BSS and BC). The animals used for EB quantification were anesthetized and received an intravenous injection of EB simultaneously to the topical challenge. The ocular extravasation of the colorant was determined by 620 nm absorbance spectrophotometry. The animals used for clinical evaluation were observed for clinical signs of the allergic reaction. EB ocular extravasation was significantly lower in the eyes treated by spaglumic acid and emedastine. The clinical scoring was consistent with EB extravasation, though the difference was not statistically significant. Spaglumic acid and emedastine seem to be the most useful drugs to reduce EB extravasation and allergic signs in an animal model of early phase allergic conjunctivitis.