Suspected risk factors for adenocarcinoma of the small bowel in Crohn's disease include surgically excluded small bowel loops, chronic fistulous disease, and male sex. Review of all seven University of Chicago cases failed to confirm any suspected risk factor. A case-control study was performed to identify possible alternatives. Each case was matched to four randomly selected controls from an inflammatory bowel disease registry matched for year of birth, sex, and confirmed small bowel Crohn's disease. Three factors were significantly associated with the development of cancer: (1) Four cancers developed in the jejunum, and jejunal Crohn's disease was associated with the development of cancer [odds ratio (OR) 8.0, 95% confidence interval (CI) 1.6-39.3]. (2) There was an association between the development of cancer and occupations known to be associated with an increased colorectal cancer risk (OR 20.3, CI 2.7-150.5). Three cases (a chemist with exposure to halogenated aromatic compounds and aliphatic amines, a pipefitter with exposure to asbestos, and a machinist with exposures to cutting oils, solvents, and abrasives) and one of 28 controls (a fireman with multiple hazardous exposures) had an occupational risk factor. (3) Among medications taken for at least six months, only 6-mercaptopurine use was associated with cancer (OR 10.8, CI 1.1-108.7). In conclusion, proximal small bowel disease, 6-mercaptopurine use, and hazardous occupations are associated with cancer of the small bowel in patients with Crohn's disease and can be added to the list of suspected risk factors.