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Background: The role of adjuvant chemoradiation therapy for ampullary carcinoma is unknown. Previous literature suggests that certain populations with high risk factors for recurrence may benefit from adjuvant chemoradiation. We combined the experience of two institutions to better delineate which patients may benefit from adjuvant chemoradiation., Methods: Patients who underwent curative surgery for ampullary carcinoma at the Johns Hopkins Hospital (n=290; 1992-2007) and at the Mayo Clinic (n=130; 1977-2005) were reviewed. Patients with <60 days of follow-up, metastatic disease at surgery, or insufficient pathologic data were excluded. The final combined study consisted of 186 patients (n=104 Johns Hopkins, n=82 Mayo). Most patients received 5-FU based chemoradiation with conformal radiation. Cox proportional hazards models were used for survival analysis., Results: Median overall-survival was 39.9 months with 2- and 5-year survival rates of 62.4% and 39.1%. On univariate analysis, adverse prognostic factors for overall survival included T3/T4 stage disease (RR=1.86, p=0.002), node positive status (RR=3.18, p<0.001), and poor histological grade (RR=1.69, p=0.011). Patients who received adjuvant chemoradiation (n=66) vs. surgery alone (n=120) showed a higher rate of T3/T4 stage disease (57.6% vs. 30.8%, P<0.001), lymph node involvement (72.7% vs. 30.0%, P<0.001), and close or positive margins (4.6% vs. 0.0%, P=0.019). Five year survival rates among node negative and node positive patients were 58.7% and 18.4% respectively. When compared with surgery alone, use of adjuvant chemoradiation improved survival among node positive patients (mOS 32.1 vs. 15.7 mos, 5 yr OS: 27.5% vs. 5.9%; RR=0.47, P=0.004). After adjusting for adverse prognostic factors on multivariate analysis, patients treated with adjuvant chemoradiation demonstrated a significant survival benefit (RR=0.40, P<0.001). Disease relapse occurred in 37.1% of all patients, most commonly metastatic disease in the liver or peritoneum., Conclusions: Node-positive patients with resected ampullary adenocarcinoma may benefit from 5-FU based adjuvant chemoradiation. Since a significant proportion of patients develop metastatic disease, there is a need for more effective systemic treatment.