The expression of Fas ligand has recently been proposed as a novel tumor escape mechanism for melanoma. To establish the characteristics of Fas ligand expression during the course of melanoma progression we performed a longitudinal study analyzing primary tumors as well as subsequently evolving metastases. In primary melanoma Fas ligand was expressed in two of 20 lesions; this expression was weak and restricted to few parts of the tumors. The Fas ligand positive primary melanomas were rather thick, i.e., 8.5 and 3.8 mm, versus a median of 2.4 mm of the remaining tumors. In contrast, for metastatic melanoma Fas ligand expression was present in six of 11 cases investigated. The metastases of primary tumors displaying Fas ligand maintained its expression. As Fas ligand positive melanoma cells are capable of inducing apoptosis in susceptible cells, e.g., Fas positive tumor infiltrating lymphocytes, we tested for the presence of apoptotic cells in situ by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. This analysis revealed that apoptotic cells were present within the Fas ligand positive tumors. The number of apoptotic cells, however, never exceeded 5% of the total cells. Thus, Fas ligand mediated apoptosis does not seem to be a major immune escape mechanism for melanoma but its expression correlates with the stage of melanoma.