Cefepime is a broad-spectrum cephalosporin with enhanced coverage against Gram-positive and Gram-negative bacteria. We did a systematic review of randomised trials that compared cefepime with another beta-lactam antibiotic, alone or with the addition of a non-beta-lactam antibiotic to both study groups. We searched Central, PubMed, Embase, Lilacs, new US Food and Drug Administration drug applications, conference proceedings, and references of the included studies. Two reviewers independently did the search and data extraction. 57 trials were included. All-cause mortality-the primary outcome-was higher with cefepime than other beta-lactams (risk ratio [RR] 1.26 [95% CI 1.08-1.49]). Sensitivity analyses by the trials' methodological quality revealed higher RRs for trials reporting adequate allocation-sequence generation (1.52 [1.20-1.92]) and allocation concealment (1.36 [1.09-1.70]). Baseline risk factors for mortality were similar. No significant differences between groups in treatment failure, superinfection, or adverse events were found. This Review provides evidence and offers possible explanations for increased mortality among patients treated with cefepime in randomised trials.