In patients with acute otitis media who had failed to improve with ampicillin therapy, 35% of Haemophilus strains isolated from the middle ear were ampicillin-resistant. Twenty-nine children (24 of whom had failed to respond to ampicillin) were treated with 40 mg erythromycin ethylsuccinate per kg per day and 100 to 150 mg sulfisoxazole per kg per day. Middle ear exudate was cultured on chocolate and 5% sheep blood agar. Twenty-three of 29 Haemophilus isolates were nontypable, 10% (3 children) were type b, 2 were Haemophilus parainfluenzae and one was not typed. All strains were resistant to ampicillin by disc susceptibility testing, and 28 of 29 strains produced beta-lactamase. The minimal inhibitory concentration of ampicillin for 15 strains ranged from 3.12 to 100 micrograms/ml (median, 6.25 micrograms/ml). The erythromycin ethylsuccinate and acetyl sulfisoxazole combination was effective in treatment of acute otitis media secondary to ampicillin-resistant Haemophilus influenzae. After 10 days of erythromycin ethylsuccinate-sulfisoxazole therapy, 18 patients had normal tympanic membranes. Of 11 with middle ear effusion, 7 cleared, 3 had recurrent otitis media within 1 month and 1 had persistent otitis media with effusion. Our experience suggests the efficacy of this combination in otitis media caused by ampicillin-resistant H. influenzae.