The majority of the tumors in periampullary region are pancreatic and ampulla of Vater carcinomas. The aim of this study was to compare histopathological features of ampulla of Vater carcinomas with pancreatic ductal adenocarcinomas and to determine diagnostic and predictive values of p16 protein and cyclin D1 expression.Tissue samples from pancreatic ductal adenocarcinomas and ampulla of Vater carcinomas were obtained from 31 patients who underwent pancreticoduodenectomy for periampullary carcinoma. The study group was composed of 12 women and 19 men. Their median age was found to be 62.32 years (range 26-85 years). The parameters analyzed in the study included lymph node metastases, perineural invasion, differentiation, duodenal invasion, grade of intraepithelial neoplasia and p16 and cyclin D1 expression in tumoral and peritumoral pancreatic tissues.In both tumor groups, the loss of p16 protein expression was significantly correlated with perineural invasion (p = 0.0001). Perineural invasion was more frequent in the pancreatic ductal adenocarcinoma group than the ampulla of Vater carcinoma group (p = 0.01). When desmoplasia and lymphoplasmacytic stromal infiltration were examined, desmoplastic reaction was significantly higher in pancreatic ductal adenocarcinomas than ampulla of Vater carcinomas (p = 0.01). No significant difference was observed between tumor groups for Cyclin D1 (p > 0.05).The results suggest that loss of p16 protein expression may be a sign for poor prognosis in periampullary cancers that is correlated mainly with perineural invasion. Desmoplastic stromal reaction may be a distinctive feature for pancreatic ductal adenocarcinoma compared with ampulla of Vater carcinoma.