We previously reported ultraviolet radiation (UVR) induction of Slug, a Snail family zinc-finger transcription factor, in the epidermis of mice; we now report that Slug-knockout mice are, unexpectedly, more resistant to sunburn than wild-type mice. There was a marked difference between the cutaneous inflammatory response in the skin of Slug-knockout and wild-type mice from 12 h to 1 week following a single exposure to 3 minimal erythemal doses of UVR. Slug-knockout mice showed a much reduced immediate increase in skin thickness and neutrophil infiltration compared to wild-type mice. However, there were as many or more intraepidermal T cells, dermal mast cells, and dermal blood vessels in the UVR-exposed skin of Slug-knockout mice as in the skin of wild-type mice. Differences in cytokine and chemokine expression following UVR appeared to account for at least some differences between the genotypes in cutaneous inflammatory response. Despite the reported antiapoptotic and antiproliferative role for Slug in some cell types, we observed little difference between the genotypes in UVR-induced keratinocyte apoptosis or proliferation. Our findings indicate an unexpected but important role for Slug in the acute cutaneous inflammatory response to UVR.