Objective: To use a randomized, prospective, multi-institutional study to compare the safety and efficacy of conventional insufflation (CIS) and valveless insufflation (AirSeal Insufflation – AIS) at the conventional pressure of 15 mm Hg in robot-assisted partial nephrectomy – a surgery where AIS has gained popularity for maintaining visualization despite suction. This study was also powered to evaluate the effect of decreasing pneumoperitoneum by 20% in the valveless system. Materials and Methods: Three high-volume institutions randomized subjects into CIS 15, AIS 15, and AIS 12 mm Hg cohorts. Endpoints included rates of subcutaneous emphysema (SCE), pneumothorax (PTX), pneumomediastinum (PMS), intraoperative end-tidal carbon dioxide (ET CO2), and peak airway pressure (PAP), as well as hospital stay, post-operative pain, and complications. Given the substantial proportion of retroperitoneal surgery, a secondary analysis evaluated the effect of surgical approach. Results: Two hundred and two patients were accrued. SCE was decreased in the AIS 12 mm Hg group (p=0.003). PTX and PMS rates were not statistically significantly different across the 3 insufflation groups. Higher rates of SCE and PMS, although not PTX, were noted in all retroperitoneal surgery groups – with lower SCE rates for AIS 12 mm Hg regardless of surgical approach. Conclusion: AIS is often preferred for complex procedures including retroperitoneal and transperitoneal robotic-assisted partial nephrectomy, for its maintenance of pneumoperitoneum despite continuous suction necessary for visualization. This study shows that AIS is safe when compared to CIS at 15 mm Hg, and shows improvement in outcomes when pneumoperitoneum pressure is reduced by 20% to 12 mmHg.