Vitamin A deficiency increases susceptibility to skin infection. However， the mechanisms by which vitamin A regulates skin immunity remain unclear. Here， we show that resistin-like molecule α (RELMα)， a small secreted cysteine-rich protein， is expressed by epidermal keratinocytes and sebocytes and serves as an antimicrobial protein that is required for vitamin-A-dependent resistance to skin infection. RELMα was induced by microbiota colonization of the murine skin， was bactericidal in?vitro， and was protected against bacterial infection of the skin in?vivo. RELMα expression required dietary vitamin A and was induced by the therapeutic vitamin A analog isotretinoin， which protected against skin infection in a RELMα-dependent manner. The RELM family member Resistin was expressed in human skin， was induced by vitamin A analogs， and killed skin bacteria， indicating a conserved function for RELM proteins in skin innate immunity. Our findings provide insight into how vitamin A promotes resistance to skin infection.