We aimed to report the latest and largest pooled analysis and evidence update to compare the perioperative, renal functional, and oncological outcomes between off-clamp and on-clamp robot-assisted partial nephrectomy (RAPN) for renal tumors.We performed a systematic literature search using PubMed, Embase, and Web of Science up to August 2021 for studies that compared the efficacy and/or safety between off-clamp and on-clamp RAPN for renal tumors. Outcomes measured were operating time, estimated blood loss (EBL), conversion rate, length of stay (LOS), complication rate, transfusion rate, long-term % decrease in estimated glomerular filtration rate (eGFR), positive surgical margin rate, and recurrence rate.A total of 21 eligible articles involving 4,493 patients (1,274 off-clamp versus 3,219 on-clamp) were included for the evidence synthesis. Baseline characteristics of the two groups were similar in all outcomes except that lower R.E.N.A.L. score and smaller tumor size were observed in the off-clamp group. Pooled analysis showed shorter operative time, higher EBL, and lower complication rate in the off-clamp group. No significant difference was observed in the conversion rate, LOS, and transfusion rate. The recurrence rates were similar in the two groups, while a lower positive surgical margin rate was observed in the off-clamp group. Finally, the off-clamp group had a superior postoperative renal functional outcome.Given the presence of heterogeneity and potential bias, urologists should select the clamp strategy based on their experience and patient-specific factors.Copyright © 2021 Huang, Cao, Chen, Chen, Li, Guo, Dong, Wei and Liu.