This study aimed to assess perioperative bleeding complications and in-hospital mortality in patients requiring emergency general surgery presenting with a history of antiplatelet (AP) versus direct oral anticoagulant (DOAC) versus warfarin use. A prospective observational study across 21 centers between 2019 and 2022 was conducted. Inclusion criteria were age 18 years or older, and DOAC, warfarin, or AP use within 24 hours of an emergency general surgery procedure. Outcomes included perioperative bleeding and in-hospital mortality. The study was conducted using analysis of variance, χ 2 , and multivariable regression models. Of the 413 patients, 221 (53.5%) reported AP use, 152 (36.8%) DOAC use, and 40 (9.7%) warfarin use. The most common indications for surgery were obstruction (23% [AP], 45% [DOAC], and 28% [warfarin]), intestinal ischemia (13%, 17%, and 23%), and diverticulitis/peptic ulcers (7%, 7%, and 15%). Compared with DOAC use, warfarin use was associated with significantly higher perioperative bleeding complication (odds ratio [OR], 4.4 [95% confidence interval (CI), 2.0-9.9]). There was no significant difference in perioperative bleeding complication between DOAC and AP use (OR, 0.7 [95% CI, 0.4-1.1]). Compared with DOAC use, there was no significant difference in mortality between warfarin use (OR, 0.7 [95% CI, 0.2-2.5]) or AP use (OR, 0.5 [95% CI, 0.2-1.2]). After adjusting for confounders, warfarin use (OR, 6.3 [95% CI, 2.8-13.9]), medical history, and operative indication were associated with an increase in perioperative bleeding complications. However, warfarin was not independently associated with risk of mortality (OR, 1.3 [95% CI, 0.39-4.7]), whereas intraoperative vasopressor use (OR, 4.7 [95% CI, 1.7-12.8]), medical history, and postoperative bleeding (OR, 5.5 [95% CI, 2.4-12.8]) were. Despite ongoing concerns about the increase in DOAC use and lack of readily available reversal agents, this study suggests that warfarin, rather than DOACs, is associated with higher perioperative bleeding complications. However, that risk does not result in an increase in mortality, suggesting that perioperative decisions should be dictated by patient disease and comorbidities rather than type of AP or anticoagulant use. Prognostic and Epidemiological; Level III.