Peripheral nerve blocks are commonly used in total knee arthroplasty (TKA). Liposomal bupivacaine is an extended-release anesthetic medication that maintains efficacy upwards of 72 hours. This study compared single-shot liposomal bupivacaine (LB) with the standard single-shot bupivacaine (SB) in a preoperative adductor canal block in TKA patients. A double-blind randomized, controlled trial at a single institution was performed in patients undergoing TKA. A standard preoperative single-shot adductor canal nerve injection was performed in 31 patients using 266 mg of liposomal bupivacaine (20 mL), whereas 32 patients received a standard formulation of 0.5% bupivacaine hydrogen chloride (20 mL). The primary outcome measure was postoperative gait velocity. Secondary outcomes included knee range of motion, pain scores, patient satisfaction, knee extension strength, opioid consumption, length of stay, and adverse events. There were no differences in baseline measures between groups. Improved pain ratings with activity (=.009) were noted on postoperative day 1 with LB (mean, 4.4; SD, 2.0) compared with SB (mean, 5.9; SD, 2.6). Fewer opioids were used with LB compared with SB on postoperative day 1 (mean, 51.2 vs 66.1; =.020) and on postoperative day 2 (mean, 39.5 vs 54.8; =.016). No statistically significant differences in gait velocity, knee range of motion, knee extension strength, or patient satisfaction occurred. Peripheral nerve blockade with a single-shot adductor canal injection demonstrated improved pain scores with activity and diminished postoperative narcotic use when using LB compared with SB in TKA patients. There may be early postoperative advantages with LB as a single-shot injection in adductor canal blockade for patients undergoing TKA. [. 2021;44(4):249-255.].