AIM: To investigate the phenotype of inflammatory bowel disease associated with primary sclerosing cholangitis (PSC-IBD). METHODS: Data from 75 PSC-IBD patients evaluated in our tertiary center between 1963 and 2006 were collected and compared to 150 IBD patients without PSC, matched for sex, birth date, IBD diagnosis date and initial disease location regarding ileal, different colonic segments, and rectum, respectively. RESULTS: While PSC-IBD patients received more 5-aminosalicylates (8.7 years/patient vs 2.9 years/patient, P < 0.001), they required less immuno-suppressors (24% vs 46% at 10 years; P < 0.001) and less intestinal resection (10% vs 44% at 10 years, P < 0.001). The 25-year cumulative rate of colectomy was 25.1% in PSC-IBD and 37.3% in controls (P = 0.004). The 25-year cumulative rate of colorectal cancer was 23.4% in PSC-IBD vs 0% in controls (P = 0.002). PSC was the only independent risk factor for the development of colorectal cancer (OR = 10.8; 95% CI, 3.7-31.3). Overall survival rate without liver transplantation was reduced in PSC-IBD patients (67% vs 91% in controls at 25 years, P = 0.001). CONCLUSION: This study confirms that patients with PSC-IBD have a particular disease phenotype independent of the initial disease location. Although their disease is less active and they use more 5-aminosalicylates, they present a higher risk of colorectal cancer.