We have recently demonstrated an age-dependent increase in the fraction of murine T cells that express high levels of the Pgp-1 surface glycoprotein, thought to be a marker for memory lymphocytes. T cells from old mice also exhibit a defect in the generation of cytoplasmic calcium signals after stimulation with Con A. To see if the increase in Pgp-1+ T cells could account for defective calcium signal generation in old mice, we carried out flow cytometric analyses to examine calcium signal production in T cells expressing high or low levels of the Pgp-1 marker. We report here that Pgp-1+ T cells, from both old and young mice, do indeed generate relatively poor Ca2+ responses when exposed either to receptor-dependent mitogens (e.g., Con A and anti-CD3) or to activators like ionomycin that bypass receptor-mediated signal transduction pathways. Both CD4 (helper) and CD8 (killer) T cells show poor calcium responses. These data suggest that the shift, with age, toward Pgp-1+ T cells, which are relatively refractory to stimuli that raise intracellular calcium concentrations, may contribute to poor cell-mediated immune function in old animals.