The role of the tumor suppressor gene p53 and proto-oncogenes mdm-2, waf-1,and bcl-2 in sporadic colorectal carcinoma (CRC) has been well investigated. However, little is known about the role of these genes in the development of ulcerative colitis-associated colorectal carcinoma (CAC). Colectomy specimens from patients with CAC, patients with ulcerative colitis (UC) and dysplasia, patients with long-standing UC without carcinoma or dysplasia, and patients with CRC were investigated in comparison to normal colon (NC) specimens from patients with diverticulosis without histologic signs of inflammation. Immunohistochemistry was performed with antibodies against p53, mdm-2, waf-1, and bcl-2; and staining was evaluated semiquantitatively with an expression of more than 20% of tumor cell nuclei or epithelial cell nuclei in nontumor specimens considered "positive." Statistical analysis was performed using Fisher's exact test. In carcinomas, p53 was positive in 50% of CRC tissues and 60% of CAC tissues without statistical difference. Positive expression of p53 was found in most high-grade dysplasia but not in low-grade dysplasia (p < 0.01). Whereas mdm-2 and bcl-2 were only sporadically expressed, waf-1 was observed in most specimens, with a high prevalence in UC without carcinoma or dysplasia (11/15). NC specimens were always negative for all antibodies. Immunohistochemical expression of p53, mdm-2, waf-1, and bcl-2 is similar for CAC and CRC. The malignant potential of dysplasia in UC is partially confirmed by a high prevalence of p53 and waf-1 expression, suggesting that CAC may develop along pathways that are different from CRC. High expression of waf-1 in nonmalignant long-standing UC has to be proved over a long-term course in its role as an independent cancer risk factor in UC patients.