Since 1980, we have observed an epidemic of otitis media caused by Branhamella catarrhalis. This event was characterized by studying the nasopharyngeal colonization of infants and children with B. catarrhalis and the clinical presentation and therapeutic outcome of acute otitis media caused by this organism. Pharyngeal colonization with B. catarrhalis was commoner in winter than summer. B. catarrhalis was present in middle-ear fluid (MEF) of 17% of children with otitis media, and was commoner in fall and winter (20%) than in spring and summer (11%, P less than .05). Seventy-five percent of isolates produced beta-lactamase (Ravasio type). In five of 20 patients, treatment with beta-lactamase-susceptible agents failed to sterilize B. catarrhalis-infected MEF. All of these five patients were infected with beta-lactamase-producing strains. The increasing prominence of antibiotic-resistant B. catarrhalis in acute otitis media may lead to a reevaluation of initial antibiotic therapy for acute otitis media, particularly in winter or in areas where colonization with such strains is prevalent.