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Background: Population-based survival and costs of pancreas adenocarcinoma patients receiving adjuvant chemoradiation and chemotherapy following pancreaticoduodenectomy are poorly understood. Methods: This retrospective cohort study used linked administrative and pathological datasets to identify all patients diagnosed with pancreas adenocarcinoma and undergoing pancreaticoduodenectomy in Ontario between April 2004 and March 2014, who received postoperative chemoradiation or chemotherapy. Stage and margin status were defined by using pathology reports. Kaplan–Meier and Cox proportional hazards regression survival analyses were used to determine associations between adjuvant treatment approach and survival, while stratifying by margin status. Median overall health system costs were calculated at 1 and 3 years for chemoradiation and chemotherapy, and differences were tested using the Kruskal–Wallis test. Results: Among 709 patients undergoing pancreaticoduodenectomy for pancreas cancer during the study period, the median survival was 21 months. Median survival was 19 months for chemoradiation and 22 months for chemotherapy. Patients receiving chemoradiation were more likely to have positive margins: 47.7% compared with 19.2% in chemotherapy. After stratifying by margin status and controlling for confounders, adjusted hazard ratio of death were not statistically different between chemotherapy and chemoradiation [margin positive, hazard ratio (HR) = 0.99, 95% confidence interval (CI) = 0.88–1.27; margin negative, HR 0.95, 95% CI 0.91–1.18]. Overall 1-year health system costs were significantly higher for chemoradiation (USD $70,047) than chemotherapy (USD $54,005) (p ≤ 0.001). Conclusions: Chemotherapy and chemoradiation yielded similar survival, but chemoradiation resulted in higher costs. To create more sustainable healthcare systems, both the efficacy and costs of therapies should be considered. [ABSTRACT FROM AUTHOR]