Trimethoprim-sulfamethoxazole (TMP-SMZ) was successful treatment for 93% of cases of acute otitis media caused by ampicillin-resistant Haemophilus influenzae studied. All 15 children in this study had symptoms of otitis media that were unrelieved by a course of ampicillin therapy, but 14 of them responded promptly to a 10-day course of TMP-SMZ. Potentially invasive type b strains of H. influenzae were isolated in cultures of the middle ear exudate of three children, all of whom responded well to TMP-SMZ therapy. The middle ear isolates of H. influenzae were sensitive in vitro to TMP-SMZ. It is concluded that TMP-SMZ is effective and convenient for the treatment of otitis media caused by ampicillin-resistant H. influenzae.