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Background: The preferred management for adenocarcinomas of the ampulla of Vater is pancreaticoduodenectomy. Factors most often associated with a poor prognosis include T stage and node status. Currently, many authorities recommend adjuvant therapy for patients with more advanced ampullary carcinomas. However, no randomized data are available, and retrospective analyses have generally failed to demonstrate a survival advantage for patients receiving adjuvant therapy. Therefore, the aim of this analysis was to determine whether adjuvant chemoradiation improved survival in patients with resected Stage IIB or III ampullary adenocarcinoma.Methods: From 1990 through 2008, 80 patients with adenocarcinoma of the ampulla of Vater underwent pancreaticoduodenectomy at our institution. The mean age was 63.2 years, and 43 were male (54%). The T stages were I (16%), II (30%), III (44%), IV (10%). Thirty-five patients (44%) had node-negative disease whereas 45 patients (56%) were node-positive. AJCC stages were I (25%), IIA (15%), IIB (36%), III (23%), IV (1%). Three patients died postoperatively (3.8%). Overall, 38 patients (48%) received adjuvant chemoradiation which generally consisted of 54 Gy external beam radiation with 5-FU as a radiosensitizer as well as 5-FU (37%), gemcitabine (42%), or FOLFOX (21%) chemotherapy usually given both before and after chemoradiation. Survival was determined from the time of surgery until death or November 2009. Kaplan-Meier methodology was used to estimate survival. Cox proportional hazards models were employed to examine the effect of prognostic factors on overall survival.Results: Overall median and 5-year actuarial survival were 36 months and 45%, respectively. Age, gender, tumor size, tumor differentiation, and use of adjuvant therapy were not significantly associated with improved survival. However, node-positive disease was prognostic for poorer overall survival (81 vs 21 months, p < 0.001). Of 45 patients with stage IIB and III disease, 32 (71%) received adjuvant therapy, and 13 patient were not treated. However, survival was significantly prolonged in this high-risk subset of patients receiving adjuvant therapy (31 vs 13 months, p < 0.01).Conclusions: Adjuvant chemoradiation following curative resection for stage IIB and III ampullary adenocarcinomas provided a statistically significant benefit in overall survival. Until randomized studies have been performed, patients with resected lymph node positive ampullary carcinoma should be strongly considered for adjuvant chemoradiation.