Objective:The aim of this study was to determine the comparative efficacy and safety between on-clamp and off-clamp partial nephrectomy in patients with renal masses.Materials and methods:This systematic review was pre-registered on The International Prospective Register of Systematic Reviews (PROSPERO) (CRD42022339127). PubMed, Scopus, and Web of Science were searched. A manual search was also conducted to avoid missing relevant studies. All observational and experimental studies reporting the comparative efficacy and/or safety of on-clamp versus off-clamp partial nephrectomy were included. Outcomes were divided into 3 categories: perioperative, functional, and oncologic outcomes. Risk of bias was assessed using the The Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) and revised Cochrane ROB-II tool for nonrandomized and randomized studies, respectively. Fixed- and random-effect models were implemented to pool the mean difference and log odds ratio of continuous and dichotomous outcomes, respectively. A leave-one-out sensitivity analysis was conducted to determine if the effect size was driven by a single study, and Egger’s regression test was used to assess publication bias.Results:Forty-two studies were meta-analyzed. The on-clamping method showed greater benefit when compared to the off-clamping technique in terms of perioperative (estimated blood loss and blood transfusion), functional (estimated glomerular filtration rate), and oncologic outcomes (tumor resection time). However, it is associated with higher risk for complications. Most studies were of moderate-to-serious risk of bias.Conclusion:On-clamping shows superiority in terms of estimated blood loss, blood transfusion, estimated glomerular filtration rate, and tumor resection time. However, it is associated with increased risk of complications. The selection of the technique should be tailored per individual case based on their comorbidities and preoperative risk profile.