Lichen sclerosus et atrophicus is a chronic inflammatory skin disease of unknown aetiology. Recent studies have indicated that autoimmune mechanisms might be involved in its pathogenesis and have suggested a role for autoreactive cytotoxic T-lymphocytes. Based on recent observations we now hypothesize that a type I interferon-driven inflammation might be involved in the pathogenesis of this disease. Lesional skin biopsies were analysed by immunohistochemistry (CD3, CD4, CD8, CD68, CD123, Tia1, Granzyme B, Myxovirus resistance A, IP10/CXCL10 and CXCR3). Sequential double staining was performed to analyse co-expression of Tia1 and CXCR3. Significant expression of Myxovirus resistance A was found, indicating type I interferon production. This expression was closely associated with the expression of the interferon-inducible protein IP10 and the recruitment of CXCR3+ cytotoxic T-lymphocytes. Plasmacytoid dendritic cells appeared to be a major source of type I interferon in lichen sclerosus et atrophicus. Interestingly, several infiltrating lymphocytes contained IP10 in their granules. This is the first study providing evidence that a type I interferon-associated recruitment of CXCR3+ cytotoxic T-lymphocytes is involved in the pathogenesis of lichen sclerosus et atrophicus. Infiltrating lymphocytes, containing IP10 in their granules, could provide an important self-perpetuating mechanism.