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Abstract Polypharmacy in people living with HIV/AIDS (PLWHA) is a rising morbidity that exacts hefty economic burden on health budgets in addition to other adverse clinical outcomes. Despite recent advances, uncertainty remains around its exact definition in PLWHA. In this systematic review and Meta-analysis, we explored relevant databases (PUBMED, EMBASE, CROI) for studies evaluating polypharmacy in PLWHA from January 2000 to August 2021 to ascertain the exact numerical threshold that defines this morbidity. Two independent reviewers extracted and reviewed relevant variables for analyses. The review included a total of 31 studies involving n = 53,347 participants with a mean age of 49.5 (SD ± 17.0) years. There was a total of 36 definitions, with 93.5% defining polypharmacy as the concomitant use of 5 or more medications. We found significant variation in the numerical definition of polypharmacy, with studies reporting it as “minor” (N = 3); “major” (N = 29); “severe” (N = 2); “excessive” (N = 1); and “higher” (N = 1). Most studies did not incorporate a duration (84%) in their definition and excluded ART medications (67.7%). A plurality of studies in PLWHA have established that polypharmacy in this cohort of patients is the intake of ≥ 5 medications (including both ART and non-ART). To standardize the approach to addressing this rising morbidity, we recommend incorporation of this definition into national and international PLWHA treatment guidelines.