Mechanical damage on the skin not only affects barrier function but also induces various immune responses, which trigger or exacerbate skin inflammation. However, how mechanical damage-induced skin inflammation is regulated remains incompletely understood. Here, we show that keratinocytes express the long-chain fatty-acid elongase Elovl6. Mice deficient in Elovl6 showed higher levels of cis-vaccenic acid (CVA) in the epidermis and severe skin inflammation induced by mechanical damage due to tape stripping than did wild-type mice. CVA accelerated tape stripping-triggered keratinocyte death and release of danger-associated molecular patterns (DAMPs) such as high-mobility group box 1 protein (HMGB-1) and IL-1α, which induced production of proinflammatory cytokines and chemokines IL-1β and CXCL-1 by keratinocytes. Our results demonstrate that Elovl6 regulates mechanical damage—triggered keratinocyte death and the subsequent dermatitis.