To assess the potential role of ras oncogene activation and P53 tumor suppressor gene mutations in the development of human prostate carcinoma, nine cases of histologically heterogeneous prostate tumors obtained from total prostatectomies were probed for these specific events. Each tumor was divided into 5 to 10 areas according to different growth or histological patterns. Targeted DNA sequences coding for ras and p53 were amplified by the polymerase chain reaction, analyzed by single-strand conformational polymorphisms, and confirmed by direct DNA sequencing. Point mutations of the ras gene were found in three of the nine tumors. Two contained K-ras codon 13 and H-ras codon 61 mutations, found in only one and three areas of each lesion, respectively. The third tumor contained two different point mutations in K-ras codons 13 and 61 in different foci of the sample. Loss of heterozygosity at the polymorphic codon 72 in the p53 gene was detected in two of four informative cases (50%) showing fragment cleavage by restriction fragment length polymorphism analysis. Mutations in p53, missense transversions, single base insertions, and two base deletions were also detected in three tumors. The present results reveal mutated ras and p53 occasionally occurring in small foci of the tumor and that genetic mutations in p53, as opposed to those in ras, are more closely associated with invasive growth of heterogeneous prostate carcinoma.