CD160 is a glycosylphosphatidylinositol-anchored cell surface molecule expressed by human circulating cytotoxic lymphocytes that correspond to the majority of natural killer cell (NK) expressing CD56(dim), TCRgammadelta lymphocytes, and to a minor CD8 T-cell subset. CD160 engagement by major histocompatibility complex class I molecules triggers by itself both cytotoxic function and cytokine production in NK lymphocytes, whereas it provides co-activating signals to TCR-induced proliferation in T CD8+ lymphocytes. In this study, we analyzed by immunohistochemistry the phenotype of lymphocytes infiltrating normal skin and inflammatory skin lesions of atopic dermatitis, contact dermatitis, and psoriasis. We identified a minor original subset of CD4+ CD160+ T cells infiltrating inflammatory lesions. We found that this lymphocyte subset localization is not restricted to the skin, as we demonstrated that CD160 transcripts could be induced in IL-2 or IL-15-activated CD4+ peripheral blood lymphocytes. Finally, we report that CD160 acts as a co-activator receptor for CD3-induced proliferation of CD4+ CD160+ T cells isolated from inflammatory skin lesions. Thus, we hypothesize that the unique CD4+ CD160+ lymphocyte subset plays a role in the pathogenesis of skin inflammation.