BACKGROUND: Empiric antibiotics active against Pseudomonas aeruginosa are recommended by professional societies for certain infections and are commonly prescribed for hospitalized patients. The effect of this practice on mortality is uncertain. METHODS: A systematic literature search was conducted using Embase, Medline, PubMed, Web of Science, Cochrane, Scopus and Google Scholar from earliest entry through 9 October 2023. We included studies of patients hospitalized with P. aeruginosa infections that compared mortality rates depending on whether patients received active empiric antibiotics. RESULTS: We found 27 studies of 12 522 patients that reported adjusted OR of active empiric antibiotics on mortality. The pooled adjusted OR was 0.40 (95% CI, 0.32-0.50), favouring active empiric antibiotics. In practice, the mortality effect of empiric antibiotics against P. aeruginosa depends on the prevalence of P. aeruginosa and baseline mortality. The estimated absolute mortality benefit was 0.02% (95% CI, 0.02-0.02) for soft tissue infections, 0.12% (95% CI, 0.10-0.13) for urinary tract infections and community-acquired pneumonia, 0.3% (0.25-0.34) for sepsis without shock, 1.1% (95% CI, 0.9-1.4) for septic shock and 2.4% (95% CI, 1.9-2.8) for nosocomial pneumonia. CONCLUSIONS: The mortality effect for empiric antibiotics against P. aeruginosa depends crucially on the prevalence of P. aeruginosa and baseline mortality by type of infection. For soft tissue infections, urinary tract infections and community-acquired pneumonia, the mortality benefit is low. Meaningful benefit of empiric antibiotics against P. aeruginosa is limited to patients with approximately 30% mortality and 5% prevalence of P. aeruginosa, which is largely limited to patients in intensive care settings.