The aim of this study was to identify prognostic factors in patients undergoing pancreatoduodenectomy with lymphadenectomy for ampullary carcinoma. The records of 46 consecutive patients with ampullary carcinoma who underwent pancreatoduodenectomy from 1988 through 2006 were retrospectively reviewed. A 98% rate of potentially curative (R0) resection was achieved. There was no 30-day mortality. Overall 5-year survival rate was 64%. Univariate analysis revealed that T3 and T4 tumor (i.e., pancreatic parenchymal invasion) (P < 0.001), lymph node metastasis (P = 0.01), and perineural invasion (P < 0.001) were significant predictors of poor prognosis. Furthermore, perineural invasion was found to be a significant independent predictor of poor prognosis by multivariate analysis (P = 0.024). Pancreatoduodenectomy with lymphadenectomy for ampullary carcinoma is a safe surgical procedure with an acceptable cure rate. The presence of perineural invasion may be useful for predicting poor prognosis in patients with ampullary carcinoma who undergo potentially curative resection.