The IL-1 system plays a key role in skin physiology and pathology. In this study, we used mutant mice lacking the type I IL-1 receptor (IL-1RI), lacking IL-1 receptor antagonist (IL-1Ra), or overexpressing the human intracellular (ic) IL-1Ra1 isoform, as well as combinations thereof, to dissect the role of the IL-1 system in phorbol 13-myristate 12-acetate (PMA)-induced skin inflammation. In wild-type (WT) mice, PMA application induced epidermal thickening and dermal inflammation. Skin IL-1α production and circulating levels of the acute-phase protein serum amyloid A (SAA) were elevated. In mice lacking IL-1RI or overexpressing icIL-1Ra1, PMA induced similar epidermal thickening as in WT mice, but dermal inflammation was partially prevented. Skin IL-1α mRNA expression was similar in PMA-treated IL-1RI−/− and WT mice, whereas the increase in serum SAA was suppressed in IL-1RI−/− mice. Interestingly, PMA-induced IL-1α mRNA expression was further enhanced by icIL-1Ra1 overexpression in an IL-1RI-dependent manner. Finally, IL-1Ra−/− mice spontaneously displayed skin lesions characterized by high IL-1β, but not IL-1α, expression. In conclusion, PMA-induced epidermal thickening and skin IL-1α expression were independent of IL-1 signaling, in contrast to dermal inflammation and systemic inflammatory response.