The risk for inflammatory bowel disease (IBD)-related colorectal cancer (CRC) remains a matter of debate. Initial reports mainly originate from tertiary referral centers, and conflict with more recent studies. Overall, epidemiology of IBD-related CRC is relevant to strengthen the basis of surveillance guidelines. We performed a nationwide nested case-control study to assess the risk for IBD-related CRC and associated prognostic factors in general hospitals. IBD patients diagnosed with CRC between January 1990 and July 2006 in 78 Dutch general hospitals were identified as cases, using a nationwide automated pathology database. Control IBD patients without CRC were randomly selected. Clinical data were collected from detailed chart review. Poisson regression analysis was used for univariable and multivariable analyses. A total of 173 cases were identified through pathology and chart review and compared with 393 controls. The incidence rate of IBD-related CRC was 0.04%. Risk factors for IBD-related CRC were older age, concomitant primary sclerosing cholangitis (PSC, relative ratio (RR) per year duration 1.05; 95% confidence interval (CI) 1.01-1.10), pseudopolyps (RR 1.92; 95% CI 1.28-2.88), and duration of IBD (RR per year 1.04; 95% CI 1.02-1.05). Using immunosuppressive therapy (odds ratio (OR) 0.3; 95% CI 0.16-0.56, P<0.001) or anti-tumor necrosis factor (TNF) (OR 0.09; 95% CI 0.01-0.68, P<0.02) was protective. We found a limited risk for developing IBD-related CRC in The Netherlands. Age, duration of PSC and IBD, concomitant pseudopolyps, and use immunosuppressives or anti-TNF were strong prognostic factors in general hospitals.