Lymphocyte proliferation induced by lectins declines drastically with age. It has been suggested that the reduction of interleukin production by lymphocytes from old individuals is responsible for the decline in proliferation. In this study, lymphocyte proliferation was stimulated by the calcium ionophore, A23187. A23187 induced the proliferation of spleen lymphocytes from rats through an interleukin-independent pathway; depletion of spleen lymphocytes of macrophages, addition of exogenous interleukin 2 (IL 2), and addition of anti-IL 2 monoclonal antibodies had no effect on the proliferation stimulated by A23187. Spleen lymphocytes from male Fischer F344 male rats of 5, 13, 22, and 30 months of age were stimulated with either concanavalin A (Con A) or A23187. A 50% decrease in Con A- and A23187-induced proliferation was observed between 5 months and 13 months of age. A23187-induced proliferation decreased only slightly between 13 months and 30 months of age (14%), while Con A-induced proliferation decreased by 34%. This is the first report to show that the induction of lymphocyte proliferation through an interleukin-independent pathway decreases with increasing age. In addition, these results suggest that a decrease in the responsiveness of cells to calcium ions might be an important factor in the age-related decline in lymphocyte proliferation.