Patients exhibiting association between vitiligo and cutaneous T-cell lymphoma (CTCL) remain rare and it is not known whether some T-cell subpopulations of CTCL in the skin are able to recognize specific melanocytic epitopes and thus induce vitiligo. The aim of our study was to determine whether T cells specific to melanocyte differentiation antigens were detectable among tumour-infiltrating lymphocytes (TIL) in the hypopigmented skin of a patient with Sézary syndrome (SS). A 71-year-old patient presented with SS and developed vitiligo during the course of her disease. Immunohistochemical studies showed staining with HMB45 and MelanA antibodies in the pigmented skin biopsy, whereas no staining was observed in the hypopigmented skin biopsy. To analyse responses to melanocyte differentiation antigens, we used a transient COS transfection assay that permits an estimation of CD8 T-cell responses against a large number of HLA/antigen combinations. This technique allowed the detection of melanocyte differentiation antigen-specific T lymphocytes, directed mainly against Melan-A/MART1 antigen in the HLA-A*23 context. Our study supports the concept that vitiligo that has developed during the evolution of a CTCL is related to the presence of a T-lymphocyte subpopulation reactive against melanocyte differentiation antigens (mainly Melan-A/MART1) present in skin lesions. The role of interferon in the induction of this T-lymphocyte subpopulation is discussed.