BACKGROUND: Single-injection interscalene brachial plexus blocks are used for analgesia for rotator cuff repair (RCR) but have limited duration. The value of adding liposomal bupivacaine (LB) to prolong single-injection interscalene blocks is unclear. The purpose of this trial is to evaluate the addition of LB to regular bupivacaine interscalene blocks for patients undergoing arthroscopic RCR. METHODS: In this prospective, randomized trial, 70 patients undergoing primary RCR with equal group allocation were randomized by random number generator to receive an interscalene block with 20 mL of 0.5% bupivacaine or 10 mL 0.5% bupivacaine plus 133 mg LB. The primary outcome was cumulative opioid consumption within 72 hours of the procedure. Secondary outcomes included maximum pain scores and quality of recovery 15 survey scores. RESULTS: 70 of the 80 randomized patients were included in final analysis following exclusion for protocol violations and loss to follow-up. Cumulative opioid consumption (oral morphine equivalents) within 72 hours in patients receiving LB was a median (IQR) of 31.9 mg (0, 73.1) compared with 45.0 mg (15.0, 108.8) among patients receiving bupivacaine alone (p=0.312). Patients receiving LB demonstrated mixed results regarding worst pain scores with improvements at 24 hours and 72 hours, but not 48 hours. CONCLUSIONS: LB added to bupivacaine interscalene blocks does not reduce opioid consumption within 72 hours following arthroscopic RCR. TRIAL REGISTRATION NUMBER: NCT03587584.