Psoriasis is a chronic and excessive inflammation of the skin and is currently incurable. The cause of psoriasis remains poorly understood and a central and cooperative role for keratinocytes and T-cells in triggering the disease is highlighted. The p63 gene encodes six different proteins with homology to the tumor suppressor protein p53 that are crucial for normal development of ectodermally derived structures such as skin and oral mucosa. In this study, we have analyzed levels of the different p63 isoforms using quantitative reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry in 15 patients diagnosed with psoriasis. Quantitative RT-PCR results showed downregulation of the full-length TAp63 in psoriatic lesions compared to both clinically normal skin from patients (P<0.001) and matched healthy controls (P<0.001); however, p63 protein levels detected by immunohistochemistry were similar. All psoriasis lesions also had detectable levels of activated Stat3, a protein indicated in development of the disease, whereas control tissue lacked this protein. The present data show a different regulation of TAp63 in psoriasis, where the discrepancy between mRNA levels and protein expression indicates a post-transcriptional regulation analogous to that seen in p53.