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Objective To compare pain outcome reports of patients undergoing hip or knee replacement who received single-injection nerve/plexus blocks with plain bupivacaine (BPV) with those of patients who received injections of buprenorphine-clonidine-dexamethasone (BCD) admixed with BPV. Design Prospective, parallel-arm, randomized, double-blind trial. Setting A single veterans’ hospital. Subjects Ninety-eight veterans scheduled for total hip or knee replacement surgery with spinal as the primary anesthetic. Methods Participants were randomized to BPV-BCD or plain BPV groups. They underwent nerve/plexus blocks in the L2–L4 and L4–S3 distributions in advance of joint replacement surgery. The primary outcome was change in pain from baseline during the postoperative day, as assessed by the total pain score on the short-form McGill Pain Questionnaire-v2 (SF-MPQ-2). Secondary outcomes were pain during movement, pain interference, range of motion, mobility, and quality of recovery. Results On postoperative day one, the SF-MPQ-2 total score for the BPV-BCD group demonstrated greater pain reduction than that of the plain BPV group (mean difference 1.8 points, 95% confidence interval 0.6 to 3.0, P = 0.003). The BPV-BCD group also had larger reductions in pain during movement in the surgical joint and less pain interference, along with increased range of hip and knee flexion, compared with the plain BPV group. Outcomes of mobility and quality of recovery were not different between groups. Conclusions Preoperative BPV-BCD blocks in the L2–L4 and L4–S3 nerve distributions for hip and knee replacements led to less pain on postoperative day one and increased knee and hip range of motion, compared with plain BPV blocks. Trial registration ClinicalTrials.gov ID NCT02891798.