The CD95 (Fas)/CD95 ligand (CD95L) system is an important mechanism triggering apoptosis, and CD95L expression has recently been implicated for immune evasion and aggressive behavior in malignancies. This study aimed to investigate CD95 and CD95L expression in lymphomas and the possible relationship with tumor cell apoptosis, with emphasis on the natural killer (NK) cell lymphomas, which are highly aggressive neoplasms and frequently exhibit tumor cell apoptosis/necrosis. Frozen sections of 82 cases of lymphomas obtained from Queen Elizabeth Hospital and Caritas Medical Center, Hong Kong, were immunostained with polyclonal anti-CD95 and anti-CD95L antibodies. The NK-cell lymphomas were also studied for apoptosis by in situ end labeling (ISEL) method, and zonal tumor cell death was evaluated semiquantitatively. The cases studied included 27 NK-, 22 T-, and 33 B-cell lymphomas. CD95 was expressed in 25 (93%) NK-, 11 (50%) T-, and 14 (42%) B-cell lymphomas. CD95L was expressed in 19 (70%) NK-, 15 (68%) T-, and 3 (9%) B-cell lymphomas. There was significant difference in the frequency of CD95 expression between B- and NK- (P < .001), and between T- and NK-cell lymphomas (P < .05), and in CD95L expression between B- and T- (P < .01) or NK-cell (P < .01) lymphomas. Zonal tumor cell death was present in 21 (78%) NK-cell lymphomas and 1 (4.5%) T-cell lymphoma and showed no correlation with CD95 or CD95L expression. ISEL analysis showed apoptosis predominantly in the viable areas in only 5 (24%) NK-cell lymphomas. In conclusion, CD95L is frequently expressed in NK- and T-cell lymphomas, but rarely in B-cell lymphomas. Zonal tumor cell death is not correlated with CD95 or CD95L expression and thus the CD95/CD95L system probably does not contribute significantly to this phenomenon. We postulate that the frequent expression of CD95L by NK- and T-cell lymphomas may mediate local or systemic tissue damage and immune evasion, and may contribute to the clinical aggressiveness of these tumors.