BACKGROUND: Postoperative pain after total knee arthroplasty (TKA) poses a major challenge. It delays mobilization, increases opioid consumption and side effects, and lengthens hospitalization. This challenge multiplies when treating an opioid-dependent population. We examined whether a novel suspended release local anesthetic, liposomal bupivacaine (LB) would improve pain control and decrease opioid consumption after TKA compared to a standard periarticular injection in opioid-dependent patients. METHODS: Thirty-eight patients undergoing TKA were randomly assigned to receive either a periarticular injection (PAI) with LB (n = 20) or with a standard PAI (including a combination of ropivacaine, clonidine, Toradol, Epinepherine, and saline; n = 18) as part of a multimodal pain management approach. All periarticular injections were done by a single surgeon. Perioperative treatment was similar between groups. Postoperative information regarding pain level was evaluated by a pain visual analog scale score. Postoperative opioid consumption was recorded. RESULTS: After controlling baseline narcotic usage before surgery, no differences were found between groups in daily postoperative narcotic usage (P = .113), average daily pain score (P = .332), or maximum daily pain score (P = .881). However, when examining pain levels separately for each day, pain visual analog scale scores were reported higher in post operative day 1 in the LB group (P = .033). CONCLUSIONS: LB was not found to be superior to standard PAI in opioid-dependent patients undergoing TKA. This patient population continues to present a challenge even with modern multimodal pain protocols.