T lymphocytes have variable sensitivity to anti-CD95 which does not correlate closely with the level of CD95 expressed. To investigate this phenomenon, we screened murine T lymphocyte cultures for their sensitivity to anti-CD95. Subclones of the S49.1 cells showed widely variable sensitivity to anti-CD95 but similar levels of CD95. The resistant clones became sensitive after treatment with actinomycin D suggesting that they expressed resistance protein(s) with a high turnover relative to the CD95 apoptosis induction machinery. Our data suggest that the resistance protein(s) are not Bcl-2, Bcl-x, Fap-1 or Bag-1. Forced, increased expression of CD95 made most of the resistant cells more sensitive, but some remained resistant suggesting that the expression of the resistant protein(s) is heterogeneous and that increased CD95 levels does not always overcome the resistance.