Objectives/Hypothesis: A reliable model of allergy has been created in the Brown Norway rat. In this model, allergen presentation to the middle ear causes functional disruption of the eustachian tube, predisposing to the development of otitis media with effusion. The purpose of this study was to study the effects of ototopical antihistamine on lipopolysaccharide (LPS)-induced otitis media in the allergic rat model. Study Design: Prospective animal-based research study. Methods: Fifteen (n = 15) rats were made allergic via sensitization to ovalbumin (OVA) by subcutaneous injection and randomized into three groups: saline (SAL) + LPS, olopatadine (OLO) + LPS, and azelastine (AZE) + LPS. Allergic rats were transtympanically injected with OVA 24 hours prior to challenge, creating a subclinical inflammatory response in which there is no visible middle ear effusion. Thirty-five microliters of test substance (SAL + LPS, OLO + LPS, or AZE + LPS) were injected into the middle ear at 0, 2, and 4 hours. Effusion was collected at 2, 4, and 6 hours. Statistical analysis was performed on effusion volume and albumin concentration. Results: Significant increase in effusion volume with respect to time was noted for the SAL + LPS group, whereas the AZE + LPS group demonstrated a decrease. Intergroup comparison revealed a significant decrease in effusion volume at hour 6, with both AZE and OLO less than LPS alone. A significant decrease in albumin concentration over time was noted in the AZE group. Intergroup comparison revealed a significant difference in albumin concentration at hour 6, with OLO significantly lower than LPS. Conclusions: Ototopical antihistamines are effective in reducing effusion volume and albumin concentration in LPS-induced otitis media in an allergic rat model. This finding supports the hypothesis that ototopic antihistamines may prove effective in treating patients with allergy-induced eustachian tube dysfunction.