Objectives: Early, empirical broad-spectrum antibiotic treatment is the established practice for febrile neutropenia. Several β-lactams are accepted for monotherapy. We asked whether patients' outcomes are influenced by the chosen β-lactam. Methods: Systematic review and meta-analysis of randomized controlled trials comparing anti-pseudomonal β-lactams administered as empirical monotherapy for febrile neutropenia, with or without vancomycin. The search included The Cochrane Library, PubMed, Embase, Lilacs databases, bibliography, conference proceedings, trial registries and FDA new drug approvals. Two reviewers independently applied selection criteria, performed quality assessment and extracted the data. Trials assessing the same β-lactam were pooled using the fixed effect model. Relative risks (RRs) with 95% confidence intervals (CIs) were calculated. The primary outcome assessed was all-cause mortality. Results: Thirty-three trials fulfilled inclusion criteria. Cefepime was associated with higher all-cause mortality at 30 days than other β-lactams (RR 1.44, 95% CI 1.06-1.94, 3123 participants). Carbapenems were associated with fewer treatment modifications, including addition of glycopeptides, than ceftazidime or other comparators. Adverse events were significantly more frequent with carbapenems, specifically pseudomembranous colitis (RR 1.94, 95% CI 1.24-3.04, 2025 participants). All-cause mortality was unaltered. Piperacillin/tazobactam was compared only with cefepime and carbapenems, in six trials. No significant differences were demonstrated with paucity of data for all-cause mortality. Conclusions: The use of cefepime for febrile neutropenia is associated with increased mortality and should be carefully considered pending further analysis. Empirical use of carbapenems entails fewer treatment modifications, but an increased rate of pseudomembranous colitis. Ceftazidime, piperacillin/tazobactam, imipenem/cilastatin and meropenem appear to be suitable agents for monotherapy.