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Background: Recent advances in chemotherapy have been shown to downsize initially unresectable colon cancers. The role of neoadjuvant therapy in duodenal adenocarcinoma, especially its effect on resectability, disease-free survival (DFS) and overall survival (OS) is unknown. Our aim was to evaluate the long-term outcome in initially unresectable patients with duodenal adenocarcinoma following neoadjuvant chemotherapy and rescue surgery.Methods: A retrospective review between 1/1994-1/2010 of all patients who underwent rescue duodenectomy following neoadjuvant therapy was performed.Results: Ten patients received neoadjuvant chemotherapy prior to surgical resection (7 men, 3 women) with a mean age of 54 years (range 45-67 years). Reasons for unresectable disease were vascular encasement in 6 patients, retroperitoneal extension of tumor abutting on the aorta or inferior venacava in 3 patients and bulky local disease causing malignant bowel obstruction in 1 patient. Six were primary presentations and 4 were local recurrences. Of the 6 primary presentations, 4 received neoadjuvant therapy with FOLFOX, one with chemoradiation with 5-FU and one with CPT-11, oxaliplatin and capecitabine. Of the 4 patients with locally recurrent disease, one had radiotherapy with 5-FU and capecitabine, one had FOLFIRI, one had CPT-11, 5-FU and leucovorin, and one had FOLFOX. All 10 patients underwent R0 resection following neoadjuvant therapy. Histologic evaluation revealed that 2 patients had complete pathologic response (1 on FOLFOX and 1 on chemoradiation with 5-FU) and one patient had only 10% viable tumor remaining after FOLFOX. Two patients had >50% decrease in tumor size. The average tumor size was 3.4 cm (range <1 cm- 4.6 cm). Eight patients had grade 3 tumors and 2 patients had grade 4 tumors. Three patients had positive lymph nodes and 7 had negative lymph nodes. Five patients had T3 tumors, 3 had T4 tumors, one had T2, and one had no residual tumor identified on pathologic evaluation. Four patients with tumors in the fourth portion (D4) and 4 patients with tumors in the third portion (D3) underwent segmental resection, while 1 patient with tumor at the second portion (D2) underwent standard Whipple resection and 1 patient with tumor at D2/D3 junction underwent standard Whipple with en bloc resection. On follow up, 5 patients are alive today (follow-up range 15-48 months) including 2 of the patients presenting with recurrent disease. Of these 5 patients, 2 had positive nodes and 3 had negative nodes. Since rescue surgery, all have no evidence of recurrent disease. Conclusion: Long-term survival can be achieved in select patients with initially unresectable duodenal adenocarcinoma. From our experience, neoadjuvant chemotherapy may improve resectability of previously unresectable duodenal adenocarcinoma.