We performed a prospective, randomized, placebo-controlled, double-blind clinical trial of antibiotic administration to treat possible occult bacteremia in febrile children. A total of 955 children aged 3 to 36 months with temperatures greater than or equal to 39.0 degrees C and no focal bacterial infection were enrolled at the emergency departments of two children's hospitals from January 1982 until July 1984. Blood samples for culture were obtained, and the children were randomly assigned to receive either oral amoxicillin or placebo and were restudied approximately 48 hours after enrollment. Data were also collected on 228 children who could not be randomly assigned. Twenty-seven of the randomly assigned children (2.8 percent) had bacteremic infections with pathogenic organisms (Streptococcus pneumoniae, Haemophilus influenzae, and salmonella). There were no differences in the incidence of major infectious morbidity associated with bacteremia between the antibiotic and placebo groups--2 of 19 patients (10.5 percent) in the antibiotic group and 1 of 8 (12.5 percent) in the placebo group--although the power for this comparison was low. Antibiotics reduced fever (P less than 0.005) and improved the clinical appearance (P = 0.07) in the children with bacteremia but not in those without bacteremia. Although there were no statistically significant differences in the incidence of side effects, diarrhea tended to occur more often in the patients treated with amoxicillin (15 vs. 11 percent, P less than 0.10). We conclude that our data do not support the routine use of standard oral doses of amoxicillin in febrile children who do not have evidence of focal bacterial disease.