The levels of cyclic adenosine 3', 5'-monophosphate (cAMP) in suspensions of unstimulated spleen cells from tumor-free 30-month old (C57BL/10Sn X C3H/HeDiSn)F1 hybrid mice averaged only 14% of that of 6-month old mice. By contrast, the level of cyclic guanosine 3', 5'-monophosphate (cGMP) in spleen cell suspensions from old mice was about 270% that of young mice. The cAMP/cGMP ratio for the unstimulated (resting) state showed a decline by 30 months to about 5% of its 6-month value. Cyclic nucleotide levels were also measured in cell suspensions from old and young mice at intervals over a two hour period following in vitro stimulation with the plant mitogens phytohemagglutinin, concanavalin-A and pokeweed mitogen. Quantitative and in some instances qualitative differences in responses were noted. These results might conceivably reflect either age-related changes in the splenic lymphoid cell subpopulations or intrinsic cellular alterations or both. It is unlikely that changes of this degree could be wholly explained by population shifts. An imbalance in cyclic nucleotide levels in both resting and stimulated lymphoid cells in older animals might contribute to the immune dysfunction known to occur with normal aging.