Studies using PPARgamma agonists in mouse skin have suggested that peroxisome proliferator-activated receptor gamma (PPARgamma) is irrelevant to cutaneous photobiology. However, in several epithelial cell lines, ultraviolet B (UVB) has been shown to induce the nonenzymatic production of oxidized phospholipids that act as PPARgamma agonists. UVB is also a potent inducer of prostaglandin E(2) (PGE(2)) production and COX-2 expression in keratinocytes and PPARgamma is coupled to increased PGE(2) production in other cell lines. In this current study, we demonstrate that PPARgamma agonists, but not PPARalpha or PPARbeta/delta agonists, induce PGE(2) production and COX-2 expression in primary human keratinocytes (PHKs). Importantly, PPARgamma agonist-induced COX-2 expression and PGE(2) production were partially inhibited by the PPARgamma antagonist, GW9662, indicating that both PPARgamma-dependent and -independent pathways are likely involved. GW9662 also suppressed UVB and tert-butylhydroperoxide- (TBH-) induced PGE(2) production in PHKs and intact human epidermis and partially inhibited UVB-induced COX-2 expression in PHKs. These findings provide evidence that PPARgamma is relevant to cutaneous photobiology in human epidermis.