Background:The HIV viral protein R (Vpr) is a multifunction protein involved in the pathophysiology of HIV-1. Recent evidence has suggested that Vpr amino acid substitutions influence the pathophysiology of HIV-1 and clinical outcomes in people living with HIV (PLWH). Several studies have linked Vpr amino acid substitutions to clinical outcomes in PLWH; however, there is no clear consensus as to which amino acids or amino acid substitutions are most important in the pathophysiology and clinical outcomes in PLWH. We, therefore, conducted a systematic review of studies investigating Vpr amino acid substitutions and clinical outcomes in PLWH.Methods: PubMed, Scopus and Web of Science databases were searched according to PRISMA guidelines using a search protocol designed specifically for this study.Results: A total of 22 studies were included for data extraction, comprising 14 cross-sectional and 8 longitudinal studies. Results indicated that Vpr amino acid substitutions were associated with specific clinical outcomes, including disease progressions, neurological outcomes and treatment status. Studies consistently showed that the Vpr substitution 63T was associated with slower disease progression, whereas 77H and 85P were associated with no significant contribution to disease progression. Conclusions:Vpr-specific amino acid substitutions may be contributors to clinical outcomes in PLWH, and future studies should consider investigating the Vpr amino acid substitutions highlighted in this review.