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Periarticular injection is becoming more commonly utilized for pain relief following total knee arthroplasty. However, we are aware of no randomized controlled trial that has investigated the efficacy of periarticular injection for pain relief after simultaneous bilateral total knee arthroplasty.We performed a randomized controlled trial of patients scheduled for simultaneous bilateral total knee arthroplasty. Seventy-one patients with 142 involved knees were randomly assigned to receive periarticular injection or epidural analgesia. Other perioperative interventions, including spinal anesthesia, surgical techniques, and postoperative medication protocols, were identical for all patients. The primary outcome was postoperative pain at rest, measured with the use of a 100-mm visual analog scale (VAS) during the initial twenty-four-hour postoperative period. The cumulative VAS score was calculated with use of the area under the curve and compared between the groups.Postoperative pain at rest, quantified as the area under the curve of serial assessments during the initial twenty-four-hour postoperative period, was significantly less in the periarticular injection group than in the epidural analgesia group (174.9 ± 181.5 mm × day compared with 360.4 ± 360.6 mm × day; p = 0.0073). The prevalences of nausea on the night of surgery and postoperative day 1 and of pruritus were significantly lower in the periarticular injection group than in the epidural analgesia group (14% and 45%, p = 0.0031; 14% and 55%, p = 0.0003; and 0% and 15%, p = 0.014, respectively).Periarticular injection was associated with better pain relief during the first twenty-four hours following simultaneous bilateral total knee arthroplasty and decreased opioid-related side effects compared with epidural analgesia. Periarticular injection may be preferable to epidural analgesia for pain relief after simultaneous bilateral total knee arthroplasty.Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.