- Background. Antibiotic overuse is of great public health concern. This study assessed whether intervention among physicians and their treated population could achieve a sustained reduction in antibiotic use, specifically in classes known to promote antibiotic resistance among children in a community setting. Methods. We performed a cluster randomized controlled multifaceted trial among 52 primary care pediatricians and the 88,000 children registered in their practices. The intervention was led by local leaders and engaged the participating physicians. It included physician focus group meetings, workshops, seminars, and practice campaigns. These activities focused on self-developed guidelines, improving parent and physician knowledge, diagnostic skills, and parent-physician communication skills that promoted awareness of antibiotic resistance. The main outcome measure was the change in annual antibiotic prescription rates (APRs) of children treated by the intervention group physicians as compared with rates among those treated by control group physicians. The study comprised a 2-year pre-intervention period, a 3-year intervention period, and a 1-year follow-up period. Mixed-effect models were used to assess risk ratios to account for the clustered study design. Results. A decrease in the total APR among children treated by the intervention physicians compared with those treated by the control physicians was observed in the first intervention year (APR decrease among control physicians, 40%; APR decrease among intervention physicians, 22%; relative risk [RR], .76; 95% confidence interval [CI], .75‐.78). This reduction crossed over all antibiotic classes but was most prominent for macrolides (macrolide prescription rate among control physicians, 58%; macrolide prescription rate among intervention physicians, 27%; RR, .58; 95% CI, .55‐.62). The effect was sustained during the 4 following years. Conclusions. Multifaceted intervention that engages the physicians in an educational process is effective in reducing APRs and can be sustained. Clinical Trials Registration. NCT01187758.