BACKGROUND: Liposomal bupivacaine (Exparel) is a long-acting local anesthetic preparation with demonstrated efficacy over placebo in reducing postoperative pain and opioid requirement. Limited comparative efficacy and cost-effectiveness data exist for its use in total knee arthroplasty (TKA) when used in a multimodal, opioid-sparing analgesic and anesthetic approach. We hypothesized that liposomal bupivacaine offers no clinical advantage over our standard of care but carries significant economic impact. METHODS: This is a prospective, randomized, single-blinded, controlled trial comparing liposomal bupivacaine periarticular injection (PAI) to our current approach including conventional bupivacaine PAI, in the setting of regional anesthesia. All adult unilateral TKA patients of the collaborating surgeon were eligible to participate in the study. Patients were randomized 1:1 to either the liposomal bupivacaine protocol or the standard-of-care protocol. All patients received regional anesthesia and standard postoperative analgesia protocols. Patients and all postoperative healthcare providers were blinded to study arm assignment. RESULTS: A total of 59 patients were enrolled per our a priori power calculation after 1 exclusion for randomization error. No significant demographic differences between the study arms were found. There was no statistically significant difference in the primary outcome of number of physical therapy (PT) sessions required to achieve home-going discharge goals (3.0 ± 1.2 vs 3.6 ± 1.3, P = .137), nor in the clinical secondary outcomes. A significant difference in medication charges was found. CONCLUSION: Our study supports earlier literature suggesting no significant clinical benefit of using liposomal bupivacaine over standard of care in TKA and underscores cost-of-care concerns with this agent.