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Introduction: Anesthetic strategies to improve postoperative pain management after Total Knee Arthroplasty (TKA) include multimodal pain management to minimize opiate requirements. Postoperatively, subcutaneous standard bupivacaine HCl is often used. Recent studies have suggested that high dose liposomal bupivacaine may result in improved outcomes. Objectives: This study aims to compare periarticular injection of 399mg (high dose) Liposomal Bupivacaine to Standard Bupivacaine in patients undergoing Total Knee Arthroplasty. Methods: We propose a phase II, single-institution, randomized, controlled, double-blinded, superiority trial with two parallel arms with a 1:1 allocation ratio. The two arms of the study will be standard bupivacaine and liposomal bupivacaine at 399mg dose. We will include patients with age >50 years, with primary knee osteoarthritis requiring TKA, ASA status 1 and 2, without opioid consumption in the last 3 months, and with signed informed consent. Exclusion criteria are history of substance abuse, uncontrolled psychiatric disorder, hepatic cirrhosis, renal failure, rheumatoid arthritis, immune arthritis, post-traumatic osteoarthritis, active malignancy or oncologic disease, pregnancy, synchronic surgical intervention, and morbid obesity with Body Mass Index (BMI) equal or greater than 40kg/m2. The primary outcome is time to first opioid rescue. Secondary outcomes include total opioid consumption, VAS scale, adverse events, GROC score, arc of motion, bupivacaine serum levels, length of stay, and mobilization. Discussion: Improving total knee arthroplasty postoperative pain without opioids decreases opioid-related side effects, reduces costs, and improves outcomes. By decreasing opiate use and complications related to them, Liposomal Bupivacaine may improve patient satisfaction as well as functional outcomes.