Progesterone decreases the cAMP level of Xenopus oocytes which had been pretreated with cholera toxin (6 nM) and IBMX (1 mM); its action is obtained either by exposure to external hormone (1 micro M) or by microinjection of 50 nl of a 1 mM progesterone solution in paraffin oil. The cAMP content can be decreased in hormone-free oocytes by the calcium ionophore A 23187 or by microinjection of calcium-calmodulin. Conversely when endogenous calcium-calmodulin is inhibited by microinjection of either anticalmodulin antibodies or fluphenazine the cAMP content is increased. In all experimental conditions (high or low levels of intracellular calmodulin), progesterone is always capable of decreasing the oocyte cAMP concentration. Our results favor the view that the cAMP content is negatively controlled, probably via an inhibition of the adenylate cyclase activity, by two parallel mechanisms: the first involves calmodulin, the second results in an action of progesterone which does not require the intermediary formation of the calcium-calmodulin complex.