Background: Trimethoprim-sulfamethoxazole (TMP-SMX) is a first-line Pneumocystis pneumonia pneumonia) (PCP) prophylaxis agent, but monthly intravenous pentamidine (IVP) is used in human immunodeficiency virus (HIV)-uninfected immunocompromised hosts because IVP is not associated with cytopenia and delayed engraftment. Method: We performed a systematic review and meta-analysis to estimate breakthrough PCP incidence and adverse reactions in HIV-uninfected immunocompromised patients receiving IVP. MEDLINE, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov were searched from their inception until 15 December 2022. Results: The pooled incidence of breakthrough PCP with IVP was 0.7% (95% CI, 0.3–1.4%, 16 studies, 3025 patients) and was similar when used as first-line prophylaxis (0.5%; 95% CI, 0.2–1.4%, 7 studies, 752 patients). The pooled incidence of adverse reactions was 11.3% (95% CI, 6.7–18.6%, 14 studies, 2068 patients). The pooled adverse event-related discontinuation was 3.7% (95% CI, 1.8–7.3%, 11 studies, 1802 patients), but was lower in patients receiving IVP monthly (2.0%; 95% CI 0.7–5.7%, 7 studies, 1182 patients). Conclusion: Monthly IVP is an appropriate second-line agent for PCP prophylaxis in certain non-HIV immunocompromised hosts, especially in patients with hematologic malignancies and hematopoietic stem cell transplant recipients. Using IVP for PCP prophylaxis as an alternative to oral TMP-SMX while patients are unable to tolerate enteral medication administration is feasible.