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To better define cell surface-related changes involved in lymphocyte activation, we studied native concanavalin A (Con A) and succinylated concanavalin A (Suc-Con A) for their effects on proliferation and cyclic nucleotide levels of human peripheral blood lymphocytes. At optimal mitogenic concentrations, the two forms of Con A induce equivalent proliferation; however, the mitogenic activity of Con A progressively decreases above 50 Mg/ml. In contrast, the mitogenic activity of Suc-Con A is not decreased even at 250 qg/ml.Lymphocytes stimulated by a range of concentrations of SueCon A (25-250 gg/ml) show progressive increases in levels of guanosine 3':5'-cyclic monophosphate (cyclic GMP) during the first 10 min of incubation. During the same period, native Con A induces initial increases in cyclic GMP; however, above 25 jsg/ml, lymphocytes treated with Con A show concentrationdependent declines in the elevated cyclic GMP levels. Although Suc-Con A has no significant effect on levels of adenosine 3': 5'-cyclic monophosphate (cyclic AMP), Con A produces increases that are concentration-and time-dependent. The concentrations of Con A responsible for the early declines in cyclic GMP and the increases in cyclic AMP levels are those which in parallel studies induce less lymphocyte proliferation. The consistent increase in cyclic GMP levels caused by both Con A and Suc-Con A suggests that cyclic GMP is involved in the induction of the proliferative response. The increase in cyclic AMP levels caused byCon A, but not by its succinylated derivative, may be responsible for the decrease in mitogenic potential observed with high doses of the native mitogen.