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Background Adding liposomal bupivacaine to brachial plexus block may improve postoperative analgesia after upper limb surgery.Objective This study aimed to assess the postoperative analgesic efficacy of adding liposomal bupivacaine to brachial plexus block compared with non-liposomal local anesthetic.Evidence review A systematic literature search was conducted in PubMed, Web of Science, EMBASE, ClinicalTrials.gov, and the Cochrane Library up to June 30, 2024. Randomized controlled trials (RCTs) that evaluated the postoperative pain scores in patients who received liposomal bupivacaine via brachial plexus block were identified. The primary outcome was resting pain scores (Numerical Rating Scale, 0–10) at 24 hours after nerve block injection derived from the random effects model. A mean difference (MD) of 1/10 was considered to represent a minimal clinically important difference in pain scores. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework was applied to examine the level of evidence.Findings 21 RCTs (1478 participants) were included. Liposomal bupivacaine was associated with statistically significant reduction in resting pain scores at 24 hours after nerve block injection compared with non-liposomal local anesthetic (MD=–1.04, 95% CI=–1.54 to –0.53, p<0.001, 95% prediction interval=–3.05 to 0.98). This was associated with significant heterogeneity (Q=107, p<0.001, I²=81%, tau 2=1.0, 95% CI=0.42 to 2.07) and a low-GRADE rating. Liposomal bupivacaine was also associated with a statistically significant reduction in resting pain scores at 48 hours and 72 hours. Opioid consumption at 0–24 hours, 25–48 hours and 49–72 hours was lower in the liposomal bupivacaine group with statistical significance (p values <0.05). Liposomal bupivacaine was associated with a lower incidence of nausea.Conclusions There is low-level evidence that liposomal bupivacaine in brachial plexus block may reduce pain intensity after upper limb surgery, but the clinical significance may be limited.