High coverage of pre-exposure prophylaxis (PrEP) will reduce HIV transmission and help end the HIV/AIDS pandemic. However, PrEP users face challenges, including long-term adherence. The study aimed to document the proportions of individuals who restart HIV PrEP after they stop and the reasons for restarting PrEP. This study is a systematic review and meta-analysis. We systematically searched CINAHL, Embase, Emcare, Global Health, Medline, Scopus, and PsychINFO for peer-reviewed with no date restrictions. A grey literature search was conducted through Google search, a search of abstract books of AIDS conferences and the websites of WHO and UNAIDS. The data search was conducted in April 2023 and updated in February 2024. Two authors extracted data on the proportion of people who stopped and then restarted PrEP, reasons for restarting, and strategies to support people restarting PrEP. Two authors appraised the data using the Joanna Briggs Institute Appraisal Tools. We used a random-effects meta-analysis to pool estimates of restarting. We conducted meta-regression to determine potential sources of heterogeneity. This study is registered with PROSPERO, CRD42023416777. However, we deviated from our original plan as we did not identify enough studies for strategies to support restarting PrEP (primary objective). Subsequently, we revised our plan to strengthen our secondary objective to quantify the proportion of people who stopped and restarted PrEP, and explore possible reasons for its heterogeneity. Of 988 studies, 30 unique studieswere included: 27 reported the proportion restarting PrEP, and of these, 7 also reported reasons for restarting PrEP, and 3 studies reported only on the reasons for restarting PrEP. No study evaluated interventions for restarting PrEP. For the meta-analysis, we included 27 studies. Most studies were from high-income countries (17/27, 63%) or the USA (15/27, 56%). Overall, 23.8% (95% CI: 15.9-32.7, I2 = 99.8%, N = 85,683) of people who stopped PrEP restarted PrEP. There was a lower proportion of restarting in studies from middle-income countries compared to high-income countries (adjusted odds ratio (aOR) 0.6, 95% CI: 0.50-0.73, p < 0.001). There was higher restarting in studies from Africa compared to the USA (aOR 1.55, 95% CI: 1.30-1.86), heterosexual populations compared to men who have sex with men or transgender women (aOR 1.50, 95% CI: 1.25-1.81, p < 0.001) and in studies defining restarting as those who had stopped PrEP for >1 month compared to those who stopped <1 month (aOR 1.20, 95% CI: 1.06-1.36, p < 0.001). Reasons for restarting PrEP included perceived higher risk for HIV acquisition and removal of barriers to access PrEP. In terms of quality assessment, overall, both randomised controlled trials had a low risk of bias, while the observational studies used in the meta-analysis had some potential risk of bias related to not explicitly addressing potential confounders (15/25, 60%) or not describing strategies to address incomplete follow-up (24/25, 96%). About a quarter of people who stopped PrEP would restart, with substantial variation across countries and populations. It is important to understand the motivations and contextual factors influencing restarting PrEP and the support systems to enable restarting PrEP for those at ongoing risk. Australian National Health and Medical Research Council.