It has been observed that certain rare alleles of the c-Ha-ras gene occur more frequently in patients with certain malignant tumors than in healthy individuals, suggesting that these alleles may serve as markers for particular types of cancer. In this study, we compared the restriction fragment length polymorphism at the c-Ha-ras gene locus in 40 patients with cirrhosis and hepatocellular carcinoma with that in 39 patients with cirrhosis and in 42 normal subjects, all of Caucasian origin. Southern blotting of leukocyte DNA from the above patients, after digestion with either BamH1 or AvaII, revealed the presence of allele fragments of different sizes, corresponding to 4 common alleles and 3 rare alleles. The occurrence of the 3 rare alleles was not significantly different in the 3 populations studied. On the other hand, 2 of the common alleles, a3 (P < 0.01) and a4 (P < 0.03), were found at a significantly higher frequency in patients with cancer than in the 2 other groups. These results suggest that, in hepatocellular carcinoma, there is no increase in the frequency of occurrence of the rare alleles of the c-Ha-ras, but that the distribution of the common alleles may be modified.