Tazarotene, a member of the new class of acetylenic retinoids, has been shown to be effective in the treatment of several hyperproliferative skin diseases, including non-melanoma skin cancer. Its effectiveness is thought to rely on the ability to activate retinoic acid receptors beta and gamma and to induce a number of downstream anti-proliferative genes. Here, we show that the p53-related gene p73 is a target of tazarotene. Indeed, tazarotene modulates the expression of the p73 gene in immortalized keratinocyte cell lines by inducing the pro-apoptotic and anti-proliferative TAp73 isoforms and by repressing the anti-apoptotic and pro-proliferative DeltaNp73 isoforms. This occurs at the transcriptional level through a coordinated action on P1p73 and P2p73 promoters that control the expression of TA and DeltaN isoforms, respectively. The selective downregulation of DeltaNp73 expression by small interfering RNA led to an enhancement of tazarotene-induced bax activation and apoptosis, whereas the downregulation of both TA and DeltaN isoforms impairs tazarotene-mediated apoptosis. These results indicate the relevance of p73 gene products in tazarotene-induced growth inhibition and effectiveness in the treatment of skin tumors.