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Background: The analgesic effect of adding liposomal bupivacaine to standard bupivacaine in supraclavicular brachial plexus block is not known. We hypothesized that addition of liposomal bupivacaine would reduce acute postoperative pain compared to standard bupivacaine alone., Methods: A randomized controlled trial was conducted. Patients and outcome assessors were blinded. Eighty patients undergoing distal radial fracture fixation under regional anesthesia with supraclavicular brachial plexus block were randomized into two groups. The liposomal bupivacaine (LB-BPB) group received 10ml of 0.5% plain bupivacaine immediately followed by 10ml of 1.33% liposomal bupivacaine (n=40). The standard bupivacaine (S-BPB) group received 20ml of 0.5% plain bupivacaine (n=40). The primary outcome was weighted area under curve (AUC) numerical rating scale (NRS) pain score at rest over the first 48 hours after surgery. Secondary outcomes included AUC scores for pain with movement, overall benefit with analgesia score (OBAS) and other functional scores., Results: For the primary outcome, LB-BPB group was associated with statistically significantly lower AUC pain score at rest (0.6 vs 1.4, p-value < 0.001) in the first 48 hours. Of the secondary outcomes, no difference between treatment groups reached statistical significance with the exception of AUC score for pain with movement (2.3 vs 3.7, adjusted p-value < 0.001) and OBAS (1.1 vs 1.7, adjusted p-value = 0.020) in the first 48 hours, as well as NRS pain score at rest (0.5 vs 1.9, adjusted p-value < 0.001) and with movement (2.7 vs 4.9, adjusted p-value < 0.001) on postoperative day (POD) 1. Differences in NRS pain scores on POD2, POD3 and POD4 did not reach the level of statistical significance. There were no statistically significant differences in sensory function., Conclusion: Liposomal bupivacaine given via supraclavicular brachial plexus block reduced pain at rest in the early postoperative period., Competing Interests: Conflict of Interest: The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Anesthesiologists.)