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Background Evidence for efficacy of single, high-dose liposomal amphotericin B (LAmB) in HIV-associated cryptococcal meningitis and histoplasmosis is growing. No systematic review has examined the safety of this regimen across multiple studies. Methods We systematically searched Medline, Scopus, and the Cochrane Library from inception to April 2023 for studies reporting grade 3 and 4 adverse events (AEs) with single high-dose LAmB vs traditional amphotericin regimens for HIV-associated fungal infections. Results Three trials (n = 946) were included. Compared with traditional regimens, single high-dose LAmB was associated with equivalent risk of grade 3 and 4 AEs (risk ratio [RR], 0.75; 95% CI, 0.53–1.06) and lower overall risk of grade 4 AEs (RR, 0.68; 95% CI, 0.55–0.86), grade 4 renal (RR, 0.43; 95% CI, 0.20–0.94) and grade 4 hematological AEs (RR, 0.46; 95% CI, 0.32–0.65). Conclusions Single, high-dose LAmB is associated with a lower risk of life-threatening AEs compared with other World Health Organization–endorsed amphotericin B–based regimens in invasive HIV–related fungal infection. [ABSTRACT FROM AUTHOR]