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To investigate the effects of topical epinastine and olopatadine on tear volume by using a mouse model.Eighty-five C57BL6 mice (170 eyes) were treated twice daily with topical ophthalmic epinastine 0.05%, olopatadine 0.1%, or atropine 1% or served as untreated controls. A thread-wetting assay was used to measure tear volume at baseline and 15, 45, 90, 120, and 240 minutes after the last instillation of the drug on days 2 and 4 of treatment.After 2 days of treatment, epinastine-treated mice showed greater mean tear volumes than olopatadine-treated mice did at 15, 45, 90, and 240 minutes, with statistical significance at 15 and 45 minutes (P<0.001). Olopatadine significantly reduced tear volume versus untreated controls at 15 and 45 minutes (P<0.001). After 4 days, tear volumes with epinastine treatment exceeded those with olopatadine treatment at all time points, with statistical significance at 45 minutes (P<0.05). Atropine rendered tears undetectable at 15, 45, and 90 minutes; tear volume returned to baseline levels at 240 minutes.Topical epinastine did not inhibit tear secretion, whereas olopatadine caused a significant decrease in tear volume. Because of its neutral impact on the lacrimal functional unit, epinastine may be an especially good choice for the treatment of allergic conjunctivitis in patients with dry eye disease or in those who are at risk for developing dry eye.