BACKGROUND: Orthopedic surgery can be performed in hospital outpatient departments (HOPDs) and ambulatory surgical centers (ASCs), as well as in traditional inpatient venues. Patients who undergo orthopedic surgery may be prescribed opioids for the management of postsurgical pain. However, the association between surgery venue, postsurgical opioid use, and health care costs remains unclear. OBJECTIVE: To compare postsurgical opioid use and health care costs associated with 6 different orthopedic surgical procedures performed at inpatient, ASC, and HOPD venues. METHODS: Using the Optum Research Database, this retrospective study analyzed commercial health care claims from adult patients in the United States undergoing specific orthopedic procedures (total knee arthroplasty, partial knee arthroplasty, total hip arthroplasty, total shoulder arthroplasty, rotator cuff repair, and lumbar spinal fusion) between April 1, 2012, and December 31, 2017. The date of the first procedure in that period was the index date; continuous insurance coverage for 12 months before the index date (baseline period) to 6 months following the index date (postsurgical period, which includes the index date) was required. Opioid use and all-cause costs were measured in the postsurgical period. Baseline patient characteristics included demographics, Quan-Charlson Comorbidity Index, and opioid use. Multivariable analysis identified factors influencing postsurgical costs and persistent opioid use (defined as ≥ 1 opioid fill within 3 days after surgery [or discharge for inpatient stay] and ≥1 additional opioid fill during the postsurgical period at least 90 days after the index date). RESULTS: The sample included 126,172 patients (mean age, 58 years; 49% female). Overall, most procedures were performed at inpatient venues (68%), followed by HOPDs (18%) and ASCs (14%); the percentage of procedures performed at ASCs increased from 12% to 17% from 2012 to 2017. Patients whose procedures were performed at ASCs reported the lowest adjusted percentage of persistent opioid use following the procedure (18%) compared with those with procedures performed at HOPDs (24%) or inpatient venues (26%). Adjusted 30-day costs were 14% and 27% lower for patients with procedures in HOPDs and ASCs, respectively, compared with inpatient venues (P < 0.001 for both), and adjusted costs over the first 90 days were similar. CONCLUSIONS: All-cause costs on the day of surgery through 30 days after surgery for these 6 orthopedic procedures were significantly lower in HOPDs and ASCs compared with inpatient venues, even after adjustment for cohort, surgery year, demographic characteristics, baseline Quan-Charlson Comorbidity Index, and any opioid use within 90 days before the procedure. Additionally, patients undergoing orthopedic surgery at ASCs had the lowest adjusted percentage of persistent opioid use compared with those undergoing surgery at HOPDs or inpatient venues. Migration of certain orthopedic procedures from inpatient venues to HOPDs or ASCs may reduce health care costs and decrease the potential for persistent opioid use. DISCLOSURES: This study and editorial support for the preparation of this manuscript was funded by Pacira BioSciences, which contracted with Optum to conduct the study. Cisternas, Korrer, and Wilson are employees of Optum. Waterman was employed with Pacira BioSciences at the time of the study. Portions of this work were presented at AMCP Nexus 2019; October 29-November 1, 2019; National Harbor, MD.