We have studied the effects of chronic treatment with recombinant interleukin-2 on the central nervous system of adult and old mice. Treatment with high doses of recombinant interleukin-2, on a schedule similar to that used in humans, was started at the age of 4 and 17 months, respectively, and ended 3 months later. At that time, all the mice were tested for acquisition of a passive-avoidance task and then sacrificed for histological examination. Three of the four groups (treated and control adults and control old mice) did not differ from one another in task performance or neuron density in frontal cortex, cerebellum, dentate gyrus or CA1-2, CA3, CA4 hippocampal areas. The old treated mice were unique in showing impairment of the mnesic functions and marked neuronal cell loss and degenerative changes limited to the hippocampal regions. Immunohistochemical studies did not show any significant amount of immunoglobulins in affected areas. Our results suggest that in old mice the impairment of the mnesic functions after recombinant interleukin-2 administration is due to hippocampal neuronal damage.