Purpose: Mild to moderate pain is common following dental implant surgeries, although severe pain is reported in some patients. This randomized, open-label trial was designed to determine the efficacy and safety of an opioid-sparing postsurgical pain management protocol with or without local infiltration of liposomal bupivacaine for full-arch implant surgery. This procedure is used in edentulous and/or failing dentition patients and involves securing four or more implants to the maxilla and/or mandible to serve as anchors for dental prostheses. Materials and Methods: Patients scheduled to undergo full-arch implant surgery were randomly assigned to receive an opioid-sparing postsurgical pain management protocol with or without liposomal bupivacaine 266 mg at the end of surgery. All patients received infiltration with ≤ 40 mL lidocaine 2% with epinephrine at the beginning of surgery and bupivacaine 0.5% with epinephrine near the end of surgery and oral opioid or nonopioid analgesics (oxycodone 5 mg tablets or ibuprofen 600 mg), as needed, postsurgically. Pain severity at the surgical site was assessed using a verbal 0 to 10 numeric rating scale (0 [no pain] to 10 [worst pain imaginable]). Patients separately assessed pain in their mandible and maxilla. Reports of treatment-emergent adverse events were collected. Results: Sixty-nine patients were randomized to the liposomal bupivacaine 266 mg (n = 34) or control group (n = 35). At all time points postsurgery for both the mandible (all P ≤ .0112) and the maxilla (all P ≤ .0083), the liposomal bupivacaine group reported significantly less cumulative pain than the control group. At the conclusion of the 7-day follow-up, patients in the liposomal bupivacaine group experienced one-third less cumulative postsurgical pain than patients in the control group. Seventy-seven percent of patients in the liposomal bupivacaine group and 80% in the control group experienced a treatmentemergent adverse event. A higher percentage of patients in the liposomal bupivacaine versus control group reported itching (15% vs 9%) and constipation (38% vs 23%). Conclusion: Patients receiving an opioidsparing postsurgical pain management protocol with liposomal bupivacaine 266 mg experienced a statistically significant reduction of postsurgical pain and clinically relevant reduction in opioid consumption. The overall incidence of treatment-emergent adverse events was comparable in patients receiving an opioid-sparing postsurgical pain management protocol with or without liposomal bupivacaine. Keywords: bupivacaine, dental implantation, liposomes, local anesthetics, non-opioid analgesics, oral surgery, pain management, postoperative pain