Protein kinase C delta (PKC-δ) protein levels are frequently low in chemically and UV-induced mouse skin tumors as well as in human cutaneous squamous cell carcinomas (SCCs). Furthermore, overexpression of PKC-δ in human SCC lines and mouse epidermis is sufficient to induce apoptosis and suppress tumorigenicity, making PKC-δ a potential tumor suppressor gene for SCCs. Here we report that PKC-δ is lost in human SCCs at the transcriptional level. We used laser capture microdissection to isolate cells from three normal human epidermis and 14 human SCCs with low PKC-δ protein. Analysis by quantitative reverse transcription-PCR revealed that PKC-δ RNA was reduced an average of 90% in the SCCs tested, consistent with PKC-δ down-regulation at the protein level. Analysis of DNA from nine of the same tumors revealed that PKC-δ gene was deleted in only one tumor. In addition, Ras-transformed human keratinocytes, which have selective down-regulation of PKC-δ at both protein and mRNA levels, had significantly repressed human PKC-δ promoter activity. Together, these results indicate that PKC-δ gene expression is suppressed in human SCCs, probably via transcription repression. Our results have implications for the development of topical therapeutic strategies to trigger the re-expression of pro-apoptotic PKC-δ to induce apoptosis in SCCs.