We compared the effect of two neuropeptides, calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP), on mitogen-induced murine splenocyte proliferation. Both neuropeptides exerted their maximal effect within 24 hr after activation by Con A. The combination CGRP-VIP caused an additive inhibitory effect on T-cell proliferation. The inhibitory effect of VIP could be correlated with a decrease in interleukin 2 (IL-2) production, whereas CGRP did not affect this production. Since we also observed an additive inhibitory effect on T-cell proliferation by the theophylline and CGRP or VIP combination, we measured the effect of each neuropeptide on intracellular cAMP production by enriched T-cells: CGRP, but not VIP, strongly stimulated cAMP synthesis. Taken together, our results indicate that inhibition of murine T-cell proliferation by CGRP and VIP is mediated by different mechanisms.