Cortactin and fascin-1 are important factors affecting progression and metastasis of carcinomas. We tested the hypothesis that cortactin and fascin expression has significant correlation with clinicopathological parameters in pancreatic and ampulla of Vater adenocarcinomas. Immunohistochemical analysis of cortactin and fascin-1 was performed in 50 pancreatic and 40 ampulla of Vater adenocarcinomas. The specimens were from 29 R0, 8 R1, and 13 palliative resections of pancreatic adenocarcinomas and 18 R0, 14 R1, and 8 palliative resections of ampulla of Vater adenocarcinomas. ‘R0’ resection is defined by complete removal of the tumor and histologically negative surgical margins and ‘R1’ resection indicates the presence of microscopically residual disease at the surgical margins. The level of expression was assessed by scoring the intensity of cytoplasmic or membranous immunostaining on a 4-point scale. Higher immunostaining scores of cortactin and fascin-1 were both significantly correlated with histological grade, American Joint Committee on Cancer (AJCC) stage, and survival rate in all patients. In conclusion, overexpression of cortactin and fascin-1 implies poorer tumor differentiation, advanced AJCC stage, and shorter survival rate in pancreatic and ampulla of Vater adenocarcinomas.