OBJECTIVE: Recommendations on treatment of acute staphylococcal osteomyelitis of children, based mostly on retrospective analyses, comprise surgical drainage, up to 6 weeks fo antimicrobials guided by the erythrocyte sedimentation rate, and the possibility of switching to the oral route only if monitoring of serum bactericidal titer is guaranteed. A prospective study was conducted to test whether the treatment could be simplified. DESIGN: Fifty pediatric cases of acute Staphylococcus aureus osteomyelitis were randomized to receive 150 mg/kg/day of cephradine divided in four doses, or 40 mg/kg/day in four doses of clindamycin. The treatment was initiated intravenously, but switched to oral administration mostly within 4 days, using the same doses. The peak antimicrobial serum inhibitory titer or bactericidal titer was not measured. The course of illness was monitored by blood leukocytes, erythrocyte sedimentation rate, and serum C-reactive protein. The follow-up was extended to 1 year posthospitalization. SETTING: Eight tertiary pediatric-orthopedic hospitals in Finland. MAIN OUTCOME MEASURE: Full recovery and remaining healthy at least 12 months from hospital discharge. RESULTS: The lower and upper extremities were affected in 72% and 8% of patients, respectively. No surgery at all or needle aspiration only was performed in 62% and drilling in 38%. C-reactive protein and the sedimentation rate normalized within 9 days and 29 days, respectively. X-ray changes developed in 68% but had no prognostic significance. The mean hospitalization time was 11 days, and the total duration of antimicrobials was 23 days. No failure has occurred nor have long-term sequelae been observed in any patient. CONCLUSIONS: Treatment of pediatric acute staphylococcal osteomyelitis can be simplified and costs reduced by keeping surgery at a minimum, shortening hospitalization and the course of antimicrobials, switching quickly to the oral route, and not monitoring serum bactericidal activity.