Background: Current guidelines of empirical antibiotic treatment for inpatients with community-acquired pneumonia recommend antibiotics whose spectrum covers intracellular (atypical) pathogens. No sufficient evidence exists to support the necessity of such coverage, whereas limiting it may reduce toxic effects, resistance, and expense. Our goal was to assess the efficacy of empirical coverage of atypical pathogens in terms of mortality and clinical and bacteriological success. Methods: Systematic review and meta-analysis of randomized, controlled trials comparing treatment regimens with and without coverage of atypical pathogens. We searched MEDLINE, EMBASE, the Cochrane Library, and references. Relative risks (RRs) with 95% confidence intervals (CIs) were pooled using the fixedeffects model. The primary outcome assessed was all-cause mortality. Results: We included 24 trials encompassing 5015 patients. We found no studies of a drug without atypical coverage that compared it with the same drug supplemented with a drug with atypical coverage; nearly all compared a β-lactam with a single quinolone or macrolide. There was no difference in mortality between the 2 arms (RR, 1.13 [95% CI, 0.82-1.54]). Regimens with coverage of atypical pathogens showed a trend toward clinical success and a significant advantage to bacteriological eradication. Both disappeared when evaluating methodologically high-quality studies alone. These regimens further showed a significant advantage in clinical success for Legionella pneumophila, whereas no advantage for pneumococcal pneumonia was seen. There was no difference between study arms in the frequency of total adverse events. Conclusion: Empirical antibiotic coverage of atypical pathogens in hospitalized patients with communityacquired pneumonia showed no benefit of survival or clinical efficacy in this synthesis of randomized trials.