To evaluate if preincision infiltration with extended-release liposomal bupivacaine provides improved overall pain relief compared with 0.25% bupivacaine after laparoscopic or robotic-assisted hysterectomy. A single-center double-masked randomized controlled trial (Canadian Task Force Classification I). A tertiary-care community hospital. Patients recruited from July 2015 through January 2016. Sixty-four patients were randomized, and 59 were analyzed for the primary outcome. Women scheduled to undergo multiport laparoscopic or robotic-assisted total hysterectomy for benign indications were randomized to receive preincision infiltration with undiluted liposomal bupivacaine or 0.25% bupivacaine. The primary outcome was overall average pain intensity by numeric rating scale (0-10) using the Brief Pain Inventory (BPI) via telephone survey on postoperative day (POD) 3. A sample size of 28 per group (N = 56) was planned to detect a 30% change in pain scores. Secondary outcomes were overall average and worst numeric pain scores on PODs 1, 2, and 14; pain scores in hospital; BPI pain interference scores; and total opioid use. There were no demographic differences between the 2 groups. For the primary outcome, we found a decrease in the average (p = .02) pain scores on POD 3 in the liposomal bupivacaine group. We also found a decrease in worst pain scores on POD 2 (p = .03) and POD 3 (p = .01). There were no differences in pain scores while in the hospital or on POD 1 or POD 14. There were no differences in BPI pain interference scores, opioid use, or reported adverse effects. For laparoscopic and robotic-assisted multiport hysterectomies, there is evidence of decreased average postoperative pain with liposomal bupivacaine compared with 0.25% bupivacaine for port-site analgesia on POD 3, but no difference in opioid use or measures of functioning.