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β-Lactam monotherapy and β-lactam plus macrolide combination therapy are both common empirical treatment strategies for children hospitalized with pneumonia, but few studies have evaluated the effectiveness of these 2 treatment approaches.To compare the effectiveness of β-lactam monotherapy vs β-lactam plus macrolide combination therapy among a cohort of children hospitalized with pneumonia.We analyzed data from the Etiology of Pneumonia in the Community Study, a multicenter, prospective, population-based study of community-acquired pneumonia hospitalizations conducted from January 1, 2010, to June 30, 2012, in 3 children’s hospitals in Nashville, Tennessee; Memphis, Tennessee; and Salt Lake City, Utah. The study included all children (up to 18 years of age) who were hospitalized with radiographically confirmed pneumonia and who received β-lactam monotherapy or β-lactam plus macrolide combination therapy. Data analysis was completed in April 2017.We defined the referent as β-lactam monotherapy, including exclusive use of an oral or parenteral second- or third-generation cephalosporin, penicillin, ampicillin, ampicillin-sulbactam, amoxicillin, or amoxicillin-clavulanate. Use of a β-lactam plus an oral or parenteral macrolide (azithromycin or clarithromycin) served as the comparison group. We modeled the association between these groups and patients’ length of stay using multivariable Cox proportional hazards regression. Covariates included demographic, clinical, and radiographic variables. We further evaluated length of stay in a cohort matched by propensity to receive combination therapy. Logistic regression was used to evaluate secondary outcomes in the unmatched cohort, including intensive care admission, rehospitalizations, and self-reported recovery at follow-up.Our study included 1418 children (693 girls and 725 boys) with a median age of 27 months (interquartile range, 12-69 months). This cohort was 60.1% of the 2358 children enrolled in the Etiology of Pneumonia in the Community Study with radiographically confirmed pneumonia in the study period; 1019 (71.9%) received β-lactam monotherapy and 399 (28.1%) received β-lactam plus macrolide combination therapy. In the unmatched cohort, there was no statistically significant difference in length of hospital stay between children receiving β-lactam monotherapy and combination therapy (median, 55 vs 59 hours; adjusted hazard ratio, 0.87; 95% CI, 0.74-1.01). The propensity-matched cohort (n = 560, 39.5%) showed similar results. There were also no significant differences between treatment groups for the secondary outcomes.Empirical macrolide combination therapy conferred no benefit over β-lactam monotherapy for children hospitalized with community-acquired pneumonia. The results of this study elicit questions about the routine empirical use of macrolide combination therapy in this population.