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Background Although increasingly administered to patients with pancreatic ductal adenocarcinoma, the role of preoperative therapy for patients with distal cholangiocarcinoma is undefined. Methods All patients with distal cholangiocarcinoma who underwent pancreatoduodenectomy between 1999 and 2014 were retrospectively reviewed. Differences in clinicopathologic characteristics and overall survival (OS) were compared between patients who underwent surgery de novo and those who received preoperative therapy. Results Twenty-one patients (46.7%) received preoperative therapy and 24 (53.3%) did not. Five-year OS rates were not statistically significantly different between patients who received preoperative therapy and those who did not (46.6% vs 49.1%, p > 0.05). On multivariate cox proportional hazards analysis, lymph node positivity was the strongest predictor of OS (HR 4.68 (95%CI 1.52–14.42)). Whereas preoperative therapy was not associated with improved OS (HR 1.06 (95%CI 0.42–2.66)), the receipt of either pre- or post-operative therapy was (HR 0.40 (95%CI 0.16–1.00)). Conclusion While these results do not support the routine administration of preoperative therapy to patients with distal cholangiocarcinoma, it may be an alternative treatment strategy appropriate for a subset of patients with high risk clinical or pathologic features.