This study compared the postoperative analgesic efficacy of liposomal bupivacaine as a single-administration adductor canal block (ACB) vs periarticular injection (PAI) for pain control after total knee arthroplasty (TKA). From May 2016 to June 2017, a total of 70 unilateral TKA patients were randomized into 2 groups: PAI (extended-release bupivacaine 266 mg [20-mL vial] with 20 mL of 0.5% bupivacaine hydrochloride and normal saline to a total volume of 120 mL) and ACB (subsartorial saphenous nerve using extended-release bupivacaine 266 mg [20-mL vial]). All patents underwent spinal anesthesia with comprehensive preemptive and postoperative multi-modal pain protocol. All opioids administered were converted to morphine equivalents. Pain was recorded at 4 to 12 hours on the day of surgery, and on postoperative days 1, 2, and 3. Patients and investigators other than the surgeon and anesthesiologist were blinded to the study. The difference in pain scores between the PAI and ACB groups was not statistically significant during the first 12 hours (day 0) after surgery or on postoperative day 1 (5.31 vs 4.26, P=.091). However, on postoperative day 3, the mean pain score increased in the ACB group and decreased in the PAI group (4.8 vs 1.83, P=.037). There was no statistically significant difference between the 2 groups regarding the accumulative daily converted morphine equivalent consumption or total consumption. Although the PAI group demonstrated longer lasting pain relief than the ACB group for the duration of the study, other outcomes were similar between the 2 groups. [Orthopedics. 2020; 43(1):e47–e53.]