We have analyzed K-ras mutations and p53 alterations in 39 tumor and nontumor samples taken from nine patients with longstanding ulcerative colitis and colorectal carcinoma. Two of nine invasive carcinomas contained a K-ras mutation. By a combination of immunohistochemistry and single-strand conformation polymorphism analysis, p53 alterations were found in three of nine carcinomas. Five of 13 dysplastic lesions harbored a mutated K-ras gene, even in the absence of detectable changes in associated invasive tumors. One single focus of dysplastic mucosa harbored concomitant K-ras and p53 gene alterations. In two patients, a K-ras mutation was detected in epithelial lesions considered to be devoid of malignant potential (villous regeneration, active colitis). Our results indicate that: 1) the prevalence of K-ras and p53 genetic alterations found in ulcerative colitis-associated colonic carcinomas appears to be lower than in sporadic carcinomas; 2) K-ras mutations can be detected in dysplasia, villous regeneration, and active colitis and affect a subpopulation of the cells composing the lesions; 3) diverse genetic alterations can be detected in the same patient and the dysplastic lesions can exhibit a different genotype than the carcinomas; and 4) at least part of active colitis and villous regeneration lesions should be considered as preneoplastic in ulcerative colitis.