We have previously shown that peroxisome proliferator activating receptor ß/d (PPAR ß/d is overexpressed in psoriasis. PPAR ß/d is not present in adult epidermis of mice. Targeted expression of PPAR ß/d and activation by a selective synthetic agonist is sufficient to induce an inflammatory skin disease resembling psoriasis. Several signalling pathways dysregulated in psoriasis are replicated in this model, suggesting that PPAR ß/d activation contributes to psoriasis pathogenesis. Thus, inhibition of PPAR ß/d might harbour therapeutical potential. Since PPAR ß/d has pleiotropic functions in metabolism, skin-targeted inhibition offer the potential of reducing systemic adverse effects. Here, we report that three selective PPAR ß/d antagonists, GSK0660, compound 3 h, and GSK3787 can be formulated for topical application to the skin and that their skin concentration can be accurately quantified using ultra-high performance liquid chromatography (UPLC)/mass spectrometry. These antagonists show efficacy in our transgenic mouse model in reducing psoriasis-like changes triggered by activation of PPAR ß/d. PPAR ß/d antagonists GSK0660 and compound 3 do not exhibit systemic drug accumulation after prolonged application to the skin, nor do they induce inflammatory or irritant changes. Significantly, the irreversible PPAR ß/d antagonist (GSK3787) retains efficacy when applied topically only three times per week which could be of practical clinical usefulness. Our data suggest that topical inhibition of PPAR ß/d to treat psoriasis may warrant further exploration.