In a prospective, randomized, open study, a combination of trimethoprim and rifampin (TMP/R) 20 mg/kg/day was compared with ampicillin (AMP) 150 mg/kg/day, both given orally twice daily for 10 days, for the treatment of 60 children who had mild community-acquired pneumonia. The control group comprised 112 healthy children. The overall duration of the disease was 8.5 +/- 3.6 days in the TMP/R group vs 6.0 +/- 1.1 days in the AMP group. Fever persisted for 7.0 +/- 1.8 days in the TMP/R-treated patients vs 5.2 +/- 1.0 days in the AMP-treated patients. At the end of the 10 days, nasopharyngeal cultures were negative in all patients in the AMP group and in 25 of the 30 patients in the TMP/R group. These five patients were clinical and microbiologic failures. We conclude that in infants and children with mild community-acquired pneumonia, treatment with AMP for 10 days is more effective than treatment with a combination of TMP/R for clinical cure and eradication of bacterial pathogens.