In this issue of Pediatrics, Biondi et al1 present a rigorous systematic review and meta-analysis of the literature on the use of antibiotics to treat community-acquired (CA) lower respiratory infections (LRIs) secondary to Mycoplasma pneumoniae (MP). Consistent with previous studies, but on a larger scale, the evidence is deemed insufficient to support or refute such treatments for MP. The following comments, although largely addressed in the article, are intended to highlight the caution that is required on the part of the reader when attempting to implement these conclusions to everyday practice. In particular, we must point out that lack of evidence of efficacy is not evidence of inefficacy when addressing current treatment paradigms. The problems of this and previous studies lie in the lack of uniformity of diagnostic methods, complicated by the fact that mixed infections with other microorganisms often go undiagnosed and contaminate any analysis of treatment efficacy. The small number of studies and their heterogeneity add to our inability to conclude either way, and therefore statements about results of MP-oriented antibiotic treatment are difficult to substantiate, particularly when applied to individual cases. MP is a common cause of CA LRI, particularly in school-aged children and adolescents. It is responsible for at least 40% of cases of CA pneumonia (CAP) and as many as 18% of cases requiring hospitalization in children.2 The diagnosis of MP infection is difficult and nonuniform, and serology and nucleic acid amplification (polymerase chain reaction) are mostly used. Few commercial serologic assays have been shown to have appropriate sensitivity and specificity.3 Conversely, polymerase chain reaction may overestimate the incidence of MP and cost considerations limit its use. These factors frequently limit or delay diagnosis and introduce arbitrariness to therapeutic decisions. ...