Actinic keratosis (AK) has been considered to be a precursor of squamous cell carcinoma (SCC). However, based on epidemiological and molecular studies, it has become questionable to regard AK as a precancerous lesion. We analyzed 37 AKs and 14 sporadic SCCs using six microsatellite markers in order to elucidate if any genetic instability or loss of heterozygosity (LOH) was implicated in tumorigenesis and progression of non-melanocytic skin tumor. Microsatellite instability (MSI) was not found in any of the AKs or SCCs indicating that genetic instability has little implication in the tumorigenesis of sporadic non-melanocytic skin tumor. LOH was found in seven of 37 lesions of AK, but in only one of 14 lesions of SCC. The significantly lower frequency of LOH than that previously reported in Caucasians suggested that the molecular pathogenesis of AKs and SCCs might be different between Japanese and Caucasians. The higher frequency of LOH in AKs than in SCCs in the present study supported the previous epidemiological and molecular studies that AK was not likely to proceed to SCC. LOH was also demonstrated in histologically normal-appearing skin in three cases suggesting that genetic alteration occurs before histological change appears in the sun-exposed skin.