CONTEXT: Emerging drug resistance threatens the effectiveness of existing therapies for pneumococcal infections. Modifying the dose and duration of antibiotic therapy may limit the spread of resistant pneumococci. OBJECTIVE: To determine whether short-course, high-dose amoxicillin therapy reduces risk of posttreatment resistant pneumococcal carriage among children with respiratory tract infections. DESIGN AND SETTING: Randomized trial conducted in an outpatient clinic in Santo Domingo, Dominican Republic, October 1999 through July 2000. PARTICIPANTS: Children aged 6 to 59 months who were receiving antibiotic prescriptions for respiratory tract illness (n = 795). INTERVENTIONS: Children were randomly assigned to receive 1 of 2 twice-daily regimens of amoxicillin: 90 mg/kg per day for 5 days (n = 398) or 40 mg/kg per day for 10 days (n = 397). MAIN OUTCOME MEASURES: Penicillin-nonsusceptible Streptococcus pneumoniae carriage, assessed in nasopharyngeal specimens collected at days 0, 5, 10, and 28; baseline risk factors for nonsusceptible pneumococcal carriage; and adherence to regimen, compared between the 2 groups. RESULTS: At the day 28 visit, risk of penicillin-nonsusceptible pneumococcal carriage was significantly lower in the short-course, high-dose group (24%) compared with the standard-course group (32%); relative risk (RR), 0.77; 95% confidence interval (CI), 0.60-0.97; P =.03; risk of trimethoprim-sulfamethoxazole nonsusceptibility was also lower in the short-course, high-dose group (RR, 0.77; 95% CI, 0.58-1.03; P =.08). The protective effect of short-course, high-dose therapy was stronger in households with 3 or more children (RR, 0.72; 95% CI, 0.52-0.98). Adherence to treatment was higher in the short-course, high-dose group (82% vs 74%; P =.02). CONCLUSION: Short-course, high-dose outpatient antibiotic therapy appears promising as an intervention to minimize the impact of antibiotic use on the spread of drug-resistant pneumococci.