Neoplastic progression in patients with chronic ulcerative colitis is characterized by the development of epithelial dysplasia, which is accompanied by genetic alterations. This study determined the time of onset of p53 and Ki-ras mutations as well as DNA aneuploidy during histological progression towards carcinoma. In all, 278 samples of 7 colectomy specimens were analyzed by flow cytometry, histology and single-strand conformation polymorphism analysis. Of the samples, 22% (61/278) were dysplastic and 43% (122/278) aneuploid, while 25% (71/278) showed p53 and 4% (11/278) Ki-ras mutations. The correlation between aneuploid status and p53 mutations varied among the patients. A strong correlation was noticed between histological progression from low-grade dysplasia to carcinoma and p53 mutations as well as DNA aneuploidy. Ki-ras mutations were found in 40% (2/5) of the carcinomatous samples. The correlation between p53 mutations and the histological status of the samples suggest the involvement of this genetic event in the development of colon cancer in patients with ulcerative colitis. In contrast to Ki-ras mutations, the appearance of p53 mutations is an early event. Therefore p53 analysis might be helpful in the classification of indefinite dysplasia and in the identification of patients at risk for cancer development. Further studies are necessary to detect the additional genetic alterations preceding the development of DNA aneuploidy.