Mycosis fungoides (MF) is the most frequent manifestation of cutaneous T cell lymphoma but its cause and pathophysiology remain unclear. Because progression of lesions is characteristically slow, we hypothesized that mycosis fungoides originates from an accumulation of lymphocytes due to defective apoptosis of skin homing T lymphocytes. In this study, we investigate possible alterations of three molecules regulating apoptosis, i.e., Fas antigen, Bax, and p53, at the genomic level in skin lesions from 44 patients with MF, as Fas mediates one of two major pathways for apoptosis of activated T cells. Fas mutations were found in six patients using a polymerase chain reaction and single-strand conformational polymorphism method followed by cloning and sequencing of abnormal polymerase chain reaction products. The mutations predict for defective transmission of the death signal in three cases. Immunohistochemistry demonstrated the lack of Fas protein expression on dermal lymphocytes in one case with Fas gene mutation predicting for a truncated death domain, whereas Fas protein was expressed by dermal lymphocytes in the other investigated cases. By contrast, no mutations of Bax or p53 were found, whereas immunohistochemistry demonstrated increased p53 expression in the nucleus of basal keratinocytes above the neoplastic infiltrate in some MF cases. These results support the hypothesis that Fas defects may play a role in the pathogenesis of MF.