PurposeOpioid-free anesthesia (OFA) is an alternative to conventional opioid-based anesthesia (OBA) in patients undergoing bariatric surgery. Several small studies and a meta-analysis have suggested advantages of OFA for bariatric surgery, but current evidence is still contradictory, and a universally accepted concept has not yet been established. The purpose of this study was to determine whether patients undergoing bariatric surgery experience less postoperative pain and better postoperative recovery when anesthetized with an OFA regimen than with an OBA regimen.Materials and MethodsThis prospective observational cohort study, conducted between October 2020 and July 2021, compared patients receiving OFA with patients receiving OBA. Patients were visited 24 and 48 h after the surgical procedure and asked about their postoperative pain using the visual analogue scale (VAS). Additionally, the quality of recovery-40 questionnaire (QoR-40) and the postoperative opioid requirements were recorded.ResultsNinety-nine patients were included and analyzed in this study (OFA:N= 50; OBA:N= 49). The OFA cohort exhibited less postoperative pain than the OBA cohort within 24 h (VAS median [interquartile range (IQR)]: 2.2 [1–4.4] vs. 4.1 [2–6.5];P≤ 0.001) and 48 h (VAS median [IQR]: 1.9 [0.4–4.1] vs. 3.1 [1.4–5.8];P≤ 0.001) postoperatively. Additionally, the OFA cohort had higher QoR-40 scores and required less opioid therapy postoperatively.ConclusionBased on our results the use of OFA for bariatric surgery results in less pain, reduced opioid requirements, and improved postoperative recovery—adding additional evidence regarding the use of OFA in everyday clinical practice.Graphical AbstractSupplementary InformationThe online version contains supplementary material available at 10.1007/s11695-023-06584-5.