Aging leads to an increase in the proportion of cells that have the surface phenotype (CD45RBlo, CD44hi) characteristic of memory T lymphocytes and also to a decline in both the production of IL-2 and the response to this lymphokine. Several groups have reported an increase, with age, in the secretion of IL-4 in short-term T cell cultures and have suggested that this increase could reflect the age-dependent accumulation of memory T cells, which are thought to be principally responsible for IL-4 production in young mice. Because the response to IL-2 declines with age, we hypothesized that IL-4 production would also decline with age if tested under conditions that promoted IL-2-driven expansion and maturation of IL-4-secreting effectors. Using a culture system in which T cells are first activated by immobilized anti-CD3 antibody for 2 days, and then cultured with anti-CD3 plus IL-2 for an additional 9-11 days, we found a 3-fold decline with age in IL-4 production by murine splenic CD4 T cells. Under these conditions memory (CD45RBlo) CD4 T cells from young mice produced 22-fold more IL-4 than the reciprocal naive (CD44lo) subset. Production of IL-4 by old T cells was also largely attributable to memory T cells, but memory cells from these old donors generated 6-fold less IL-4 in extended cultures than memory cells from young donors. Cultured memory (but not naive) T cells increase in number over a 9-day interval, but the amount of expansion by young memory cells is 4-fold higher than that for old cells. We conclude that the production of IL-4 by memory T cells declines with age under conditions that promote IL-2-driven proliferation and differentiation.