Using molecular diagnostic methods, the prevalence of Mycoplasma pneumoniae was the highest among hospitalized children aged 10-17 years admitted with community-acquired pneumonia; 12% required intensive care. Macrolide resistance was infrequent. Clinical presentations could not differentiate M. pneumoniae from other etiologies. Abstract Background The epidemiology of Mycoplasma pneumoniae (Mp) among US children (<18 years) hospitalized with community-acquired pneumonia (CAP) is poorly understood. Methods In the Etiology of Pneumonia in the Community study, we prospectively enrolled 2254 children hospitalized with radiographically confirmed pneumonia from January 2010-June 2012 and tested nasopharyngeal/oropharyngeal swabs for Mp using real-time polymerase chain reaction (PCR). Clinical and epidemiological features of Mp PCR-positive and -negative children were compared using logistic regression. Macrolide susceptibility was assessed by genotyping isolates. Results One hundred and eighty two (8%) children were Mp PCR-positive (median age, 7 years); 12% required intensive care and 26% had pleural effusion. No in-hospital deaths occurred. Macrolide resistance was found in 4% (6/169) isolates. Of 178 (98%) Mp PCR-positive children tested for copathogens, 50 (28%) had ≥1 copathogen detected. Variables significantly associated with higher odds of Mp detection included age (10-17 years: adjusted odds ratio aOR, 10.7 95% confidence interval {CI}, 5.4-21.1 and 5-9 years: aOR, 6.4 95% CI, 3.4-12.1 vs 2-4 years), outpatient antibiotics ≤5 days preadmission (aOR, 2.3 95% CI, 1.5-3.5), and copathogen detection (aOR, 2.1 95% CI, 1.3-3.3). Clinical characteristics were non-specific. Conclusions Usually considered as a mild respiratory infection, Mp was the most commonly detected bacteria among children aged ≥5 years hospitalized with CAP, one-quarter of whom had codetections. Although associated with clinically nonspecific symptoms, there was a need for intensive care in some cases. Mycoplasma pneumoniae should be included in the differential diagnosis for school-aged children hospitalized with CAP.