The Fas receptor (APO-1/CD95) is capable of inducing apoptosis of lymphoid cells and is expressed in some non-Hodgkin's lymphomas (NHLs). Fas expression is up-regulated at the surface of normal B cells upon triggering of the CD40 receptor. In this report, we investigated the sensitivity of NHLs to Fas-mediated apoptosis induced by anti-Fas monoclonal antibodies (MAbs) and its possible modulation by CD40 ligation in 18 NHL biopsy samples of various histological subtypes. Flow cytometric analysis showed that the fraction of Fas-expressing lymphoma cells was highly variable from sample to sample (from 1% to 93%, mean value 46%). The frequency of apoptotic cells was not significantly increased upon treatment with an anti-Fas MAb compared with control MAb in the 18 NHL cases analysed. The sensitivity of lymphoma cells to Fas-mediated apoptosis was correlated neither with the histological subtypes nor with the level of Fas expression. Activation of neoplastic B cells by CD40 ligation resulted in significant increases in Fas expression and Fas-induced apoptosis among the five B-NHL cases tested. The overall increase in apoptotic rates was moderate and remained lower in tumour samples than in control CD40-activated normal tonsil B cells. Altogether, our results indicate that the sensitivity to Fas-induced apoptosis is null or weak in NHL cells, irrespective of their histological subtype, and that it can be increased to a moderate and variable degree by CD40 ligation on neoplastic B cells. This may be an impediment to the development of Fas-based therapies for NHLs.