Otitis media with effusion (OME) and acute otitis media (AOM) continue to be a significant source of morbidity in the United States, as they account for more than 3.5 billion dollars in annual costs, and OME is the sixth most common reason for an emergency department visit. The efficacy of antihistamines in the treatment of OME/AOM has been thoroughly refuted in the literature during the past three decades. However, most studies to date have used first-generation antihistamines with or without decongestants. We propose that second-generation antihistamines may have increased efficacy in the treatment of OME/AOM because of their greater selectivity for histamine receptors and lack of anticholinergic activity. Further clinical trials may be warranted, as medical treatment with second-generation antihistamines, if proven more efficacious, may reduce the need for antibiotic treatment and surgical intervention.