Trigger digit release (TDR) performed in an office-based procedure room (PR) setting minimizes surgical costs compared with that performed in an operating room (OR); yet, it remains unclear whether the rates of major complications differ by setting. We hypothesized that surgical setting does not have an impact on the rate of major complications after TDR. Adult patients who underwent isolated TDR from 2006 to 2015 were identified from the MarketScan commercial database (IBM) using the provider current procedural terminology code 26055 with a concordant diagnosis on the same claim line (International Classification of Diseases, ninth revision, clinical modification 727.03). The PR cohort was defined by presence of a place-of-service code for an in-office procedure without OR or ambulatory center revenue codes, or anesthesiologist claims, on the day of the surgery. The OR cohort was defined by presence of an OR revenue code. We identified major medical complications, surgical site complications, as well as iatrogenic neurovascular and tendon complications within 90 days of the surgery using International Classification of Diseases, ninth revision, clinical modification diagnosis and/or current procedural terminology codes. Multivariable logistic regression was used to compare the risk of complications between the PR and OR groups while controlling for Elixhauser comorbidities, smoking, and demographics. For 7,640 PR and 29,962 OR cases, the pooled rate of major medical complications was 0.99% (76/7,640) and 1.47% (440/29,962), respectively. The PR setting was associated with a significantly lower risk of major medical complications in the multivariable analysis (adjusted odds ratio 0.76; 95% confidence interval 0.60-0.98). The pooled rate of surgical site complications was 0.67% (51/7,640) and 0.88% (265/29,962) for the PR and OR cases, respectively, with no difference between the surgical settings in the multivariable analysis (adjusted odds ratio 0.81; 95% confidence interval 0.60-1.10). Iatrogenic complications were infrequently observed (PR 5/7,640 [0.07%]; OR 26/29,962 [0.09%]). Compared with performing TDR in the OR using a spectrum of commonly used anesthesia types, performing TDR in the PR using local-only anesthesia was associated with a comparably low risk of major medical complications, surgical complications, and iatrogenic complications. Prognostic II.