Despite the fact that cancer of the pancreas constitutes the fourth leading cause of cancer deaths in the United States, it has long been neglected by epidemiologists. This is a retrospective study undertaken in 142 patients with adenocarcinoma of the pancreas, 11 with islet cell cancer, and 10 with cancer of the ampulla of Vater. The results were evaluated and interpreted in line with a review of the literature. The data indicated that this cancer predominated among males, particularly at ages under 50, and was significantly associated with cigarette smoking. There was a suggestive association with cigar smoking. Among females, a significant relationship to early-onset diabetes was found, and an association with a history of chclecystectomy was suggested. Based on the epidemiologic and pathologic data, a working hypothesiswas presented: The bile might contain carcinogens originating fromtobacco, occupational environment, and possibly diet, and cause cancer on reflux into the pancreatic duct.