Cellular DNAs from 64 human hepatocellular carcinomas (HCCs) and 4 human HCC cell lines were studied for gross structural alterations in c-myc and c-Ha-ras proto-oncogenes. A 12th codon mutation of the c-Ha-ras gene in the DNA of one tumor tissue and a 3 to 4-fold amplification of the c-myc gene in that of 2 tumor tissues were found. There was no gross DNA rearrangement of c-myc and c-Ha-ras genes or significant gene amplification of the c-Ha-ras gene in any of the tumor tissues or cell line DNAs. Although these results do not exclude the possibility that more subtle changes occur in these proto-oncogenes that play some role in human hepatocarcinogenesis, the 12th codon mutation of the c-Ha-ras gene and gross structural alterations, such as DNA rearrangement or gene amplification of c-myc and c-Ha-ras genes, appear to occur in a minority of human HCCs.