It is unknown whether colorectal cancer (CRC) in patients with inflammatory bowel disease (IBD) behaves differently from regular CRC in patients without IBD. A case-control study was conducted to compare CRC in patients with and without underlying IBD. The Department of Veterans Affairs (VA) maintains a computerized file of all hospital discharges among U.S. military veterans since 1970. This file accrues the data of 1 million hospital discharges per year. All patients with IBD and all patients with CRC who had been discharged from a VA hospital between 1981 and 1993 were selected. The influence of various risk factors on the occurrence of CRC in IBD and its mortality in patients with and without IBD was tested by logistical regression analyses. Of the 11,446 subjects with IBD, 371 had colon cancer. CRC was diagnosed in 52,243 subjects without IBD. CRC patients with IBD were 7 yr younger than those without IBD, but in patients with Crohn's disease, more cancers were located in the proximal colon (chi 2 = 18.10, df = 5, p = 0.003). The occurrence of CRC in IBD was influenced by the following risk factors: age [odds ratio (OR) = 1.45, 95% confidence interval (CI) = 1.35-1.57], sclerosing cholangitis (OR) = 3.41, CI = 2.03-5.73), and history of a disease associated with consumption of nonsteroidal anti-inflammatory drugs (NSAID) (OR = 0.84, CI = 0.65-1.09). Sex, race, and type of IBD did not exert a significant influence on the development of cancer. Cancer-related mortality was influenced by the following risk factors: age (OR = 1.16, CI = 1.14-1.18), male gender (OR = 1.23, CI = 1.06-1.44), white race (OR) = 0.97, CI = 0.96-0.99), and history of NSAID consumption (OR = 0.68, CI = 0.65-0.72). Presence of IBD was not associated with a significant influence on CRC mortality (OR = 1.00, CI = 0.70-1.43). CRC affects IBD patients at a younger age and is characterized by a more proximal localization when compared with CRC of non-IBD patients. NSAID exert a protective influence against CRC in patients with IBD similarly as in patients without IBD. Sclerosing cholangitis is associated with a strong risk of developing colon cancer in patients with IBD.