Purpose To compare the safety of on- vs off-clamp robotic partial nephrectomy (RAPN). Methods 302 patients with RENAL masses ≤ 10 were randomized to undergo on-clamp (150) vs off-clamp (152) RAPN (CLOCK trial—ClinicalTrials.gov NCT02287987) at seven institutions by one experienced surgeon per institution. Intra-operative data, complications, and positive surgical margins were compared. Results Due to a relevant rate of shift from the assigned treatment, the per-protocol analysis only was considered and the data from 129 on-clamp vs 91 off-clamp RAPNs analyzed. Tumor size (off-clamp vs on-clamp, 2.2 vs 3.0 cm, p  < 0.001) and RENAL score (5 vs 6, p  < 0.001) significantly differed. At univariate analysis, no differences were found regarding intra-operative estimated blood loss (off- vs on-clamp, 100 vs 100 ml, p  = 0.7), post-operative complications rate (19% vs 26%, p  = 0.2), post-operative anemia (Hb decrease > 2.5 g/dl 26% vs 27%, p  = 0.9; transfusion rate 3.4% vs 6.3%, p  = 0.5; re-intervention due to bleeding 1.1% vs 4%, p  = 0.4), acute kidney injury (4% vs 6%, p  = 0.8), and positive surgical margins (3.5% vs 8.2%, p  = 0.1). At multivariate analysis accounting for tumor diameter and complexity, considering the on-clamp group as the reference category, a significant difference was noted in the off-clamp group exclusively for blood loss (OR 0.3, 95% CI 0.09–0.52, p  = 0.008). Conclusions The on-clamp and off-clamp approaches for RAPN showed a comparable safety profile.