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To determine the efficacy of liposomal bupivacaine compared to placebo for postoperative pain control in patients undergoing operative fixation of ankle fractures.Prospective single-blinded randomized control trial.Academic Medical Center.After Institutional Review Board (IRB) approval, 76 patients who sustained an acute ankle fracture (OTA/AO 44A-C) requiring operative fixation met inclusion criteria.Patients were randomly assigned to 1 of 2 groups, control (local intraoperative sterile saline injection under general anesthesia) or interventional (local intraoperative liposomal bupivacaine and bupivacaine injection under general anesthesia). Injections were administered in a standardized fashion and included injection of a 1:1 mixture of a 40 mL solution consisting of 1.3% Exparel and sterile saline (interventional) or a 40 mL injection of normal saline (control) into the surrounding periosteal, peritendinous, surrounding muscles and subcutaneous tissue of the surgical incision(s).Pain medications administered and pain according to the Visual Analogue Scale was recorded at scheduled postoperative time points: 4, 24, 48, 72, and 336 hours (14 days).Thirty-nine patients were randomized to the control group and 37 to the interventional group (mean age = 42 ± 15 years), with no statistically significant differences between groups with regards to severity of injury and patient demographics. Pain scores were significantly lower in the interventional group versus control up to 2 weeks after surgery. Percocet ingestion at 4 hours was significantly lower in the interventional group (0.7 vs. 1.3, P = 0.004), while it approached significance at 48 hours postoperatively (2.8 vs. 3.69, P = 0.07). No other significant differences were noted for Percocet ingestion postoperatively at other time points assessed. The overall satisfaction with pain control was not statistically different between the 2 groups (P = 0.93).Local intraoperative infiltration of liposomal bupivacaine administered with standard bupivacaine for ankle fractures requiring Open Reduction Internal Fixation (ORIF) affords improved pain relief in the immediate postoperative period resulting in a reduction in Percocet ingestion, with resultant effects seen up to 2 days postoperatively. Continued investigation of this drug for use with extremity fractures is warranted.Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.