In the present study, we investigated the mechanisms of the resistance to CD95-mediated cell death and the effects of interferon-gamma in modulating the susceptibility to CD95-induced apoptosis of human astroglioma cells. We found that interferon-gamma administration sensitized cancer cells to CD95-mediated apoptosis. The mechanism underlying this sensitization appeared to be associated with a framework of cell changes, including up-regulation of death receptor at the cell surface, pro-apoptotic molecule Bax and Bak over-expression and mitochondria hyperpolarization, as is known to be associated with cell sensitization to apoptosis. An involvement of the proteasome activity in the mechanism of sensitization by interferon-gamma was also detected, probably as a result of the differing expression of catalytic proteasome subunits. Taken together, these findings suggest that interferon-gamma could represent a promising candidate for modulating astroglioma cell apoptotic susceptibility.