Objective: This multicenter retrospective study aimed to analyze the clinicopathological features of duodenal adenocarcinoma (DA) and identify prognostic factors for postoperative survival. Methods: Demographic characteristics, clinicopathological features, treatment outcomes and survival of DA patients undergoing surgical treatment at 18 Chinese medical centers from January 2012 to December 2023 were retrospectively analyzed. Results: Among the 2 056 DA patients included, 46.8% (963) had extra-ampullary DA (EA-DA), and 53.2% (1 093) had peri-ampullary DA (PA-DA). The 1-, 3-, and 5-year overall survival (OS) rates for patients who underwent radical surgery were 93.2%, 71.0%, and 57.2%, respectively. The median overall survival was 76 months, and the median progression-free survival (PFS) was 65 months. No differences in survival were observed between the laparotomy group and minimally invasive surgery (MIS) group either before or after propensity score matching (OS: 76 vs. 75 months before PSM, P=0.986; OS: 75 vs. 75 months after PSM, P=0.602). Furthermore, there were no significant differences between-group in operation time and postoperative complications (P＞0.05). The MIS group experienced less intraoperative blood loss and shorter hospital stays. The multivariate Cox regression analysis revealed that advanced age (HR=1.43,95% CI:1.18-1.73), elevated carbohydrate antigen 19-9 levels (HR=1.24,95% CI:1.02-1.51), perineural invasion (HR=1.44,95% CI:1.14-1.81), vascular invasion (HR=1.35,95% CI:1.07-1.71), advanced T stage (T3-4 vs. T1-2:HR=1.86,95% CI:1.49-2.31), regional lymph node metastasis (HR=1.93,95% CI:1.58-2.36), preoperative biliary drainage (HR=1.26,95% CI:1.04-1.53), intraoperative blood loss (HR=1.34,95% CI:1.11-1.62), clinically significant postoperative pancreatic fistulas (HR=1.53,95% CI:1.12-2.09), and postoperative hemorrhage (HR=1.62,95% CI:1.14-2.29) were independent risk factors for poor prognosis after surgery (all P＜0.05). Conclusions: Radical surgery is associated with favorable overall survival among DA patients, and no difference in survival is observed between EA-DA and PA-DA patients. MIS is a reliable alternative for DA treatment.