Previous work has established that aging in mice leads to an accumulation of T cells that express high levels of P-glycoprotein, a plasma membrane pump that mediates multiple drug resistance in tumor cells but whose function in normal T cells is still obscure. Pgp+ cells seem to be functionally defective: isolated from the CD4 memory population of young mice, they are unresponsive to T cell receptor-dependent stimuli in tests for proliferation and cytokine production. The proliferative defect can, however, be overcome by exposure to PMA plus the calcium ionophore ionomycin, suggesting that the Pgp+ cells may have a specific defect in calcium signal generation. We show here that Pgp+ T cells, from young or old mice, do indeed show smaller changes in intracellular calcium ion concentration than Pgp- cells, when activated either by Con A, anti-CD3 antibodies, or ionomycin. The difference between Pgp+ and Pgp- cells is apparent even in experiments on isolated CD4 memory T cells from young mice and thus is not simply a consequence of the age-dependent increase in memory cell numbers. Although the molecular basis for the abnormality in calcium signal generation by Pgp+ cells is still uncertain, our data suggest that the effect could be due to inter-subset differences in levels of sorcin, a 22 kDa cytoplasmic protein that is co-expressed with P-glycoprotein in many tumor cells and which binds free calcium ion with high affinity. Sorcin levels are higher in Pgp+ CD4 cells than in Pgp- CD4 cells of young mice and increase with age in CD4 cells, consistent with the hypothesis that sorcin interferes with calcium signals in the age-sensitive Pgp+ T cell subset.