BACKGROUND AND OBJECTIVE: Children with community-acquired lower respiratory tract infection (CA-LRTI) commonly receive antibiotics for Mycoplasma pneumoniae. The objective was to evaluate the effect of treating M. pneumoniae in children with CA-LRTI. METHODS: PubMed, Cochrane Central Register of Controlled Trials, and bibliography review. A search was conducted by using Medical Subject Headings terms related to CA-LRTI and M. pneumoniae and was not restricted by language. Eligible studies included randomized controlled trials (RCTs) and observational studies of children ≤17 years old with confirmed M. pneumoniae and a diagnosis of CA-LRTI; each must have also compared treatment regimens with and without spectrum of activity against M. pneumoniae. Data extraction and quality assessment were completed independently by multiple reviewers before arriving at a consensus. Data were pooled using a random effects model. RESULTS: Sixteen articles detailing 17 studies were included. The most commonly selected primary outcome was symptomatic improvement. Nine studies examined M. pneumoniae treatment in CA-LRTI secondary to M. pneumoniae, and 5 RCTs met criteria for meta-analysis. The suggested pooled risk difference of 0.12 (95% confidence interval, −0.04 to 0.20) favoring treatment was not significantly different and demonstrated significant heterogeneity. Limitations included substantial bias and subjective outcomes within the individual studies, difficulty interpreting testing modalities, and the inability to correct for mixed infections or timing of intervention. CONCLUSIONS: We identified insufficient evidence to support or refute treatment of M. pneumoniae in CA-LRTI. These data highlight the need for well-designed, prospective RCTs assessing the effect of treating M. pneumoniae in CA-LRTI.