The roles of cyclic AMP and calcium in the transduction of the mitogenic effects of central nervous system axolemma and myelin-enriched fractions on cultured Schwann cells were examined. Cyclic AMP levels were not elevated in axolemma or myelin-stimulated Schwann cells, but were increased when stimulated with cholera toxin, an adenyl cyclase activator. The mitogenicity of axolemma and myelin was markedly reduced by 2.5 mM citrate, a calcium chelator, and 10 uM trifluoroperazine, an inhibitor of calmodulin. Treatment of Schwann cells with several tumor-promoting phorbol esters caused significant enhancement of the mitogenicity of the axolemma and myelin preparations. These data suggest that the mitogenic effects of axolemma and myelin are not mediated by cyclic AMP, but may be mediated by calcium ions.