Two lesions, actinic keratosis (AK) and squamous cell carcinoma in situ (CIS), are believed to be precursors of squamous cell carcinoma (SCC) of the skin. These lesions can serve as an excellent model system for studying genetic changes associated with the inception of skin SCC. In the present study, five such lesions of the skin, three AKs and two AK+CIS, from three patients were short-term cultured and analyzed cytogenetically. One of the patients (case 3) had also an SCC in addition to three premalignant lesions. All lesions, but one, showed clonal karyotypic abnormalities. The recurrent changes identified were numerical, that is, +7 and +20. The structural rearrangements found in three AK were different, but it could be noted that the distal part of the long arm of chromosome 4 was involved in two AK and the SCC of case 3A. It was also interesting that chromosome 1 participated in structural rearrangements in three AK with band 1p31 being involved in two tumors. The karyotypic profile of these lesions is compared with that of skin SCC; it turns out that the general patterns are different in the sense that the SCC more often have complex karyotypes and display unbalanced aberrations involving the centromeric regions. Some karyotypic similarities between the SCC and their precursors are revealed. The fact that the structural rearrangements involving chromosomal band 3p13 and the centromeric region of chromosome 3 in AK are common features for many types of malignant tumors, including skin SCC, indicates that these changes are early genetic events associated with malignant transformation.