Use of conventional opioids for postoperative pain is associated with increased adverse events (ORAEs) in high-risk patients such as the elderly (≥ 65 years) or obese (BMI ≥ 30kg/m2) affecting outcomes and compromising analgesia. Oliceridine, a new class of μ-opioid receptor IV agonist, is selective for G-protein signaling (achieving analgesia) with limited recruitment of β-arrestin (associated with ORAEs). We estimated the cost-effectiveness of oliceridine vs morphine for postoperative pain in high-risk patients. We compared costs & outcomes of patients managed with demand dosing (DD) of oliceridine (0.35mg and 0.5mg) to those with morphine (1mg), using a decision tree with a 24-hour time horizon and sample population of 1,000 surgeries for each arm. Three common and costly ORAEs; respiratory depression (SpO2<90%, RD), vomiting, and somnolence. Costs were enumerated as differences in cost of analgesics and resources utilized to manage these AEs within 24 hours post-surgery. Risk ratios (RR) were based on AE rates observed in two pivotal controlled Phase-3 studies. The RRs were then applied to AE rates observed in the elderly (≥ 65 years) and obese (BMI ≥ 30kg/m2) patients from an open-label Phase-3 observational study of oliceridine. Costs of all analgesics and antiemetics were tabulated based on rates observed in Phase-3 studies. Standard cost weights from national discharge data and literature-sources were used to estimate hospital costs & costs per AE. Average price for oliceridine was set to $100/day and morphine, $15/day. In the high-risk patient group, use of oliceridine resulted in 201 fewer AEs (vs morphine), and $459,496 lower cost of AEs. The overall savings on cost of care were estimated at $363,944 ($907,115 for oliceridine vs $1,271,059 for morphine) for each treated population of 1000 patients. Use of oliceridine in high-risk surgical patients provides a favorable health economic outcome compared to morphine.