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Some studies suggest better outcomes with macrolide therapy for critically ill patients with community-acquired pneumonia. To further explore this, we performed a systematic review of studies with mortality endpoints that compared macrolide therapy with other regimens in critically ill patients with community-acquired pneumonia.Studies were identified via electronic databases, grey literature, and conference proceedings through May 2013.Using prespecified criteria, two reviewers selected studies; studies of outpatients and hospitalized noncritically ill patients were excluded.Two reviewers extracted data and evaluated bias using the Newcastle-Ottawa Scale. Random effects models were used to generate pooled risk ratios and evaluate heterogeneity (I2).Twenty-eight observational studies (no randomized control trials) were included. Average age ranged from 58 to 78 years and 14–49% were women. In our primary analysis of 9,850 patients, macrolide use was associated with statistically significant lower mortality compared with nonmacrolides (21% [846 of 4,036 patients] vs 24% [1,369 of 5,814]; risk ratio, 0.82; 95% CI, 0.70–0.97; p = 0.02; I2 = 63%). When macrolide monotherapy was excluded, the macrolide mortality benefit was maintained (21% [737 of 3,447 patients] vs 23% [1,245 of 5,425]; risk ratio, 0.84; 95% CI, 0.71–1.00; p = 0.05; I2 = 60%). When broadly guideline-concordant regimens were compared, there was a trend to improved mortality and heterogeneity was reduced (20% [511 of 2,561 patients] mortality with beta-lactam/macrolide therapy vs 23% [386 of 1,680] with beta-lactam/fluoroquinolone; risk ratio, 0.83; 95% CI, 0.67–1.03; p = 0.09; I2 = 25%). When adjusted risk estimates were pooled from eight studies, macrolide therapy was still associated with a significant reduction in mortality (risk ratio, 0.75; 95% CI, 0.58–0.96; p = 0.02; I2 = 57%).In observational studies of almost 10,000 critically ill patients with community-acquired pneumonia, macrolide use was associated with a significant 18% relative (3% absolute) reduction in mortality compared with nonmacrolide therapies. After pooling data from studies that provided adjusted risk estimates, an even larger mortality reduction was observed. These results suggest that macrolides be considered first-line combination treatment in critically ill patients with community-acquired pneumonia and support current guidelines.