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Background Adding neuraxial to general anesthesia (GA) has been associated with improved perioperative outcome after orthopedic surgery. Presuming a similar effect in major abdominal surgery we studied its effect on perioperative outcome in open colectomy patients. Materials and methods Retrospective study using the Premier Perspective database (n = 98,290 elective open colectomies, 2006-2012). Multilevel multivariable logistic regression models measured the association between anesthesia type (GA or general and neuraxial anesthesia combined [GNA]) and perioperative outcome with odds ratios (OR) and 95% confidence intervals (CI). Outcomes were thromboembolism, acute myocardial infarction, postoperative infection, postoperative ileus, cerebrovascular events, blood transfusion, admission to an intensive care unit, and mechanical ventilation. Results GA was used in 93.9%, GNA in 6.1%, with a similar Charlson comorbidity index between the groups (2.66 versus 2.72, respectively; P = 0.121). The multivariable analyses showed GNA (versus GA) to be associated with a significantly decreased risk for thromboembolism (OR 0.74; CI 0.58-0.93) and cerebrovascular events (OR 0.67; CI 0.51-0.88), whereas the association was nonsignificant for wound infections, pneumonia, and mechanical ventilation. However, GNA use was significantly associated with increased risk for acute myocardial infarction (OR 2.74; CI 2.19-3.43), urinary tract infection (OR 1.35; CI 1.21-1.50), postoperative ileus (OR 1.17; CI 1.09-1.26), blood transfusion (OR 1.12; CI 1.01-1.24), and admission to intensive care unit (OR 1.32; CI 1.22-1.43). Conclusions We found no clear pattern of consistent favorable results for patients undergoing their open colectomy under GNA. Further prospective research is needed to help identify those who are more likely to benefit from GNA use and its mechanism of actions. [ABSTRACT FROM AUTHOR]