Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL) and arises from the accumulation and clonal proliferation of epidermotropic, CD4+/CD45RO+ (helper/memory) T lymphocytes. Loss of CD8+ CTLs within MF lesions is associated with poor prognosis and disease progression. Because T-lymphocyte apoptosis is controlled mainly through the Fas/Fas ligand (FasL) pathway and tumor cells may escape immune surveillance by expressing FasL, triggering apoptosis of tumor-infiltrating T lymphocytes, we studied the role of this system in MF. T-cell subsets, Fas/FasL expression, and apoptosis were evaluated in normal and lesional skin biopsy specimens from 21 patients with all stages of MF and in cultured CTCL cell lines (MJ, HUT78, and HH) using immunohistochemistry, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and Western blotting. MF lesions and paired, clinically "normal," uninvolved skin showed increased numbers of both TUNEL-positive epidermal keratinocytes (n = 13; F = 31.146; P < 0.01, ANOVA) and dermal lymphocyte infiltrates (n = 13; F = 15.825, P < 0.01, ANOVA) compared with the normal control skin. FasL expression was highest in lesional epidermal keratinocytes, in CTCL tumor cell lines, and in dermal tumor lymphocytes in MF lesions compared with uninvolved skin. FasL colocalized with CD45RO+ cells. CD8+ cells in or adjacent to CD45RO+ cells were positively labeled by TUNEL for apoptosis. In addition, CD8+ cell numbers were decreased in areas in which FasL+ tumor cells were abundant (2.01 +/- 0.86%) compared with non-FasL expressing areas (13.53 +/- 3.54%; P < 0.02). These results suggest that a potential mechanism of tumor immune escape in MF is FasL-mediated apoptosis of infiltrating CD8+ CTLs.