Engagement of Fas (APO-1, CD95), a member of the tumor necrosis factor receptor superfamily, can induce apoptotic cell death. However, Fas engagement also can costimulate lymphocyte proliferation. The physiologic regulation of these two outcomes is poorly understood. Here, we have used two systems, the first in vitro and the second in vivo, to demonstrate that naïve and memory CD4(+) T cells display dichotomous responses to Fas ligation. Naïve CD4(+) T cells (CD44(lo), CD45RB+, CD62L+) die as a consequence of Fas ligation in the presence of anti-CD3 antibody, whereas memory T cells (CD44(hi), CD45RB-, CD62L-), freshly isolated from the same starting population and subjected to the same stimulation conditions, are costimulated to proliferate by Fas ligation. In vitro, we demonstrate that CD28-mediated signals or T helper 1 and T helper 2 differentiation cytokines alter the response of naïve T cells, but not of memory T cells, to Fas ligation. In vivo experiments in hen egg lysozyme (HEL) T cell receptor transgenic mice show that CD4(+) T cells from HEL-naïve mice are killed by Fas ligation, but CD4(+) T cells from long-term HEL-exposed mice are costimulated by Fas ligation. Thus, the physiological outcome of Fas ligation in CD4(+) T cells is determined primarily by the antigenic history of the T cell.