OBJECTIVE: The purpose of this prospective, randomized, single-blind trial was to assess the clinical efficacy of a single intramuscular dose of ceftriaxone compared with 10 days of oral trimethoprim-sulfamethoxazole (TMP-SMZ) in treating acute otitis media (AOM). METHODS: Children aged 3 months through 3 years diagnosed with AOM (signs of acute illness plus evidence of middle-ear effusion) were randomized to treatment with either a single intramuscular dose of ceftriaxone (maximum dose of 50 mg/kg) or 10 days of oral trimethoprim-sulfamethoxazole (8 mg of TMP and 40 mg of SMZ/kg/day in two divided doses). Children were evaluated at scheduled visits on days 3, 14, and 28, and the parents were telephoned on day 5. Children were assessed as cured, improved, or failed on day 3, and as cured or failed on days 14 and 28. Children ill at other times during the study period were, if possible, seen and assessed by the study team. RESULTS: Of 596 children enrolled during the study period, 484 were evaluable. Characteristics of evaluable subjects did not differ significantly by drug. On day 3, 223/241 children in the ceftriaxone group (92.5%) and 231/243 (95.1%) in the TMP-SMZ group were cured or improved. On day 14, 158/197 (80.2%) in the ceftriaxone group and 174/212 (82.1%) in the TMP-SMZ group were cured. On day 28, 108/136 (79.4%) in the ceftriaxone group and 124/155 (80%) in the TMP-SMZ group were cured. Persistence of middle-ear fluid did not differ between groups at day 14 (55% in the ceftriaxone group vs 47% in the TMP-SMZ group; P = .16) or at day 28 (39% vs 43%; P = .48). Pain at the injection site persisting at day 3 occurred in 8.4% of children receiving ceftriaxone. New diarrhea was more common in the ceftriaxone group (23.6% vs 9.2%; P < .001). CONCLUSION: A single intramuscular dose of ceftriaxone is comparable in clinical efficacy to 10 days of oral TMP-SMZ for treatment of AOM.