© 2022Background: Virtual reality-based therapies is proposed in the rehabilitation of people with MS (pwMS). This systematic review aimed to summarize the effectiveness of virtual reality-based (VR) therapy on fear of falling (FoF) in pwMS. Methods: PubMed (via MedLINE), the Cochrane Library, CINAHL, Scopus, Web of Science, Google Scholar, and ProQuest databases were systematically searched from inception until August 24, 2021. Randomized controlled trials (RCTs) examining the effect of VR therapy on FoF in pwMS as a primary or secondary outcome measure were selected. Potential articles were screened for eligibility and data were extracted by 3 independent reviewers. The methodological quality of the included studies was assessed using the PEDro scale and the risk of bias was independently assessed by three reviewers using the Cochrane Collaboration Risk of Bias tool. Raw (unstandardized) mean differences and standard deviations of the differences in the included studies were combined, and the overall mean effect size was calculated via a fixed-effects model for this study. Results: Four RCTs with 140 participants were included in this review and meta-analysis. The studies included generally have a low or unclear risk of bias, and the quality of the methodology is low or high. The meta-analysis confirmed that VR therapy could reduce FoF in pwMS; VR therapy promoted improvement greater than conventional exercises/balance exercises or no intervention (MD, 2.98 95% CI 0.27 to 5.70; p = 0.0313). Conclusions: This study suggested that VR therapy could be an effective rehabilitative tool for reducing FoF in pwMS. However, due to the limited number of studies included, this result should be interpreted with caution.