Mutations on the KRAS gene occur early during pancreatic duct cell carcinogenesis and have been identified in up to 90% of ductal adenocarcinoma. However, the functional role of KRAS mutations in the malignant transformation of normal pancreatic duct epithelial cells into cancer cells remains unknown. We have developed an in vitro model for KRAS transformation using near-normal HPV-16E6E7-immortalized human pancreatic ductal epithelial (HPDE-E6E7) cells. The expression of mutant KRAS(G12V) in HPDE cells by retroviral transduction resulted in weak tumorigenic transformation, with tumors formed in 50% of immune-deficient scid mice implanted by these KRAS-transformed cells. The model provides an opportunity to dissect further the molecular and cellular mechanisms associated with human pancreatic duct cell carcinogenesis.