A decrease in mouse oocyte cAMP occurs during commitment to resume meiosis (R. M. Schultz, R. R. Montgomery, and J. R. Belanoff, 1983, Dev. Biol. 97, 264-273). Experiments described in this report were performed to ascertain if oocyte cyclic nucleotide phosphodiesterase (PDE) is involved in this decrease. PDE activity was found in extracts of mouse oocytes. The activity appeared soluble and not membrane bound. For each of three different PDE inhibitors, a positive correlation was found between the ability of increasing concentrations of each compound to inhibit PDE in oocyte extracts and to inhibit germinal vesicle breakdown (GVBD). Moreover, the more potent the PDE inhibitor, the more effectively it inhibited GVBD. The possibility that calmodulin (CaM) plays a role in maturation was examined since CaM modulates PDE activity in other systems. About 0.3% of total oocyte protein is CaM as determined by radioimmunoassay and activation of exogenous PDE. A CaM-dependent step in maturation was suggested since the CaM inhibitors trifluoperazine and calmidizolium inhibited GVBD in a dose-dependent manner. In addition, the CaM inhibitors W7 and W13 inhibited GVBD at lower concentrations than the less-active corresponding congeners W5 and W12. Oocyte extracts contained a CaM-modulated PDE. Activity was inhibited about 50% by addition of EGTA, and fully restored by addition of exogenous CaM and excess calcium. cAMP hydrolysis was inhibited in a dose-dependent manner by either trifluoperazine, calmidizolium, or W7; maximal inhibition was also about 50%. CaM-modulated PDE, however, did not appear to be the target for the effects of CaM inhibitors on GVBD, since concentrations of W7 that inhibited maturation did not inhibit cAMP hydrolysis in the oocyte. Results from these studies suggest that oocyte PDE is involved in the decrease in cAMP associated with resumption of meiosis, but that the CaM-dependent step occurs subsequent to or concurrently with the drop in cAMP.