SummaryObjectiveThe objective was to evaluate the comparative effectiveness of beta‐lactam monotherapy and beta‐ lactam/macrolide combination therapy in the outpatient management of children with community‐acquired pneumonia (CAP).MethodsThis retrospective cohort study included children, ages 1–18 years, with CAP diagnosed between January 1, 2008 and January 31, 2010 during outpatient management in the Geisinger Health System. The primary exposure was receipt of beta‐lactam monotherapy or beta‐lactam/macrolide combination therapy. The primary outcome was treatment failure, defined as a follow‐up visit within 14 days of diagnosis resulting in a change in antibiotic therapy. Logistic regression within a propensity score‐ restricted cohort was used to estimate the likelihood of treatment failure.ResultsOf 717 children in the analytical cohort, 570 (79.4%) received beta‐lactam monotherapy and 147 (20.1%) received combination therapy. Of those who received combination therapy 58.2% of children were under 6 years of age. Treatment failure occurred in 55 (7.7%) children, including in 8.1% of monotherapy recipients, and 6.1% of combination therapy recipients. Treatment failure rates were highest in children 6–18 years receiving monotherapy (12.9%) and lowest in children 6–18 years receiving combination therapy (4.0%). Children 6–18 years of age who received combination therapy were less likely to fail treatment than those who received beta‐lactam monotherapy (propensity‐adjusted odds ratio, 0.51; 95% confidence interval, 0.28, 0.95).ConclusionChildren 6–18 years of age who received beta‐ lactam/macrolide combination therapy for CAP in the outpatient setting had lower odds of treatment failure compared with those who received beta‐lactam monotherapy. Pediatr Pulmonol. 2016;51:541–548. © 2015 Wiley Periodicals, Inc.