Several investigators have postulated that the activation of the Harvey-ras (rasH) gene is the initiating event in mouse skin carcinogenesis. In support of this speculation, Roop et al. (Nature, 323, 822-824, 1986) have shown that papillomas developed from skin grafts of cultured keratinocytes in which the v-rasH gene had been introduced by a defective retroviral vector. Using the same technique we have analyzed the cytogenetic profile of primary mouse epidermal cultures bearing the activated ras gene and of the tumors generated by skin grafts of the same cells. The epidermal cultures infected with the replication-defective virus which incorporated the v-rasH gene into a packaging-defective Moloney murine leukemia virus did not show any detectable karyotypic abnormalities. These cells presented a diploid/tetraploid configuration similar to uninfected controls. Furthermore, papillomas produced by skin grafts of these cells also showed euploid chromosomal profiles. On the other hand, two carcinomas that arose spontaneously from pre-existing papillomas showed 80% aneuploid cells and aneuploid stem lines. It appears, from these results, that the activated rasH gene is able to generate benign lesions without the involvement of further gross genomic alterations, but that such alterations may be associated with malignant conversion.