It has been demonstrated that in monocyte/T cell co-cultures activated with recall antigens, cytotoxic T cells were generated which are able to reduce the number of antigen-presenting monocytes. In previous studies we could show that a minor subset of monocytes, the Fc gamma receptor I-negative (CD64-) monocytes, exhibits significantly higher antigen-presenting capacity than the main population of monocytes (> 90%) which are Fc gamma receptor I-positive (CD64+). Therefore, we addressed the question whether they are also differentially susceptible to T cell-mediated killing. In the present study we demonstrate that the CD64- monocyte subset is more resistant to killing by antigen-activated T cells than CD64+ monocytes, as indicated by a higher viability and recovery of CD64- monocytes. This mechanism involves CD95 (Fas) antigen, since monocyte death in co-cultures with antigen-activated T cells could be partially reduced by blocking anti-Fas monoclonal antibodies (mAb). In agreement with this finding, although CD95 antigen was expressed on CD64+ and CD64- monocytes at comparable levels, killing of CD64- monocytes by activating anti-Fas mAb was lower than of CD64+ monocytes.