The benefit of adjuvant radiotherapy (RT) for resected pancreatic adenocarcinoma remains controversial after randomized clinical trials. In this national-level US study, a propensity score (conditional probability of receiving RT) was used to adjust for potential confounding in nonrandomized designs from treatment group differences. Patients were identified from the Surveillance, Epidemiology, and End Results (SEER) registry (1988-2005 dataset). Multivariate analyses to determine the effect of RT on overall survival were performed using propensity-adjusted Cox proportional hazards and Kaplan-Meier analyses. In total, 5676 patients with resected pancreatic adenocarcinoma were identified, and 40.8% of those patients had received adjuvant RT. Univariate predictors of survival included age, race, marital status, disease stage, tumor size, tumor extension, tumor grade, lymph node status, year of diagnosis, type of resection, and receipt of RT (all P < .002). In a Cox model, independent predictors of improved survival included white race, married status, earlier stage, smaller tumors, well differentiated tumors, negative lymph node (N0) status, recent diagnosis, and receipt of RT (all P < .05). In a propensity-adjusted proportional hazards regression, the benefit of adjuvant treatment that included RT remained significant after adjusting for the likelihood of receiving RT (hazard ratio, 0.773; 95% confidence interval, 0.714-0.836; P < .0001). Within all 5 propensity strata, Kaplan-Meier survival differed significantly (P < .0001 [lowest and highest probability strata] and P = .0165 [middle stratum with a "pseudorandom" probability of RT]). Adjuvant RT for resected pancreatic adenocarcinoma was associated with a significant survival advantage in a large national database, even after using propensity score methods to adjust for differences between treatment groups. The authors concluded that adjuvant RT should be considered for all appropriate patients who have resected pancreatic adenocarcinoma.