We investigated the aberrant promoter methylation status of 12 genes in skin lesions, both malignant (basal cell carcinomas (BCCs), n=68 and squamous cell carcinomas (SCCs), n=35) and non-malignant (tags, n=58) skin lesions and compared the results of lesions from sun exposed (SE) and sun protected (SP) regions. Methylation was studied using a methylation specific PCR (MSP) and methylation of CDH1 was also measured using a semi-quantitative fluorescence based real-time MSP method. The methylation index (MI) was calculated as the methylated fraction of the genes examined. In this report, we found high frequencies of methylation of several known or suspected tumor suppressor genes in tags and skin cancers. Among the 12 genes, for the cadherin genes CDH1 and CDH3 and for two of the laminin 5 encoding genes LAMA3 and LAMC2 methylation frequencies greater than 30% were noted in one or more specimen types. We investigated whether methylation was tumor related. Surprisingly, the differences in the methylation profile of genes among the three specimen types were modest, and the MI, indicators of overall methylation frequencies, was nearly identical. However, significant differences were noted in the frequencies of methylation among the three specimen types for the genes RASSF1A (P=0.002), CDH1 (P=0.007) and one or more of three CAD genes (P=0.02). Methylation was highly significantly related to sun exposure, and sun protected specimens had little or no methylation. As methylation of CDH1 was completely SE specific we analyzed all the skin samples using a semi-quantitative real-time PCR assay for the CDH1 gene. The concordance between standard MSP and real-time MSP for all the samples (n=161) was 75% (P<0.0001). While weak signals were detected in the SP samples by real time PCR, the differences between SE and SP specimens were 148 fold for tags and 390 fold for BCCs. These differences were highly significant (P<0.0001). These findings suggest that methylation commences in UV exposed skin at a relatively early age and occurs in skin prior to the onset of recognizable preneoplastic changes.