The phosphodiesterase inhibitors RO-201724/1 and 1-methyl-3-isobutylxanthine (MIX) stimulate a rapid increase in cyclic GMP content in rat pancreas; the latter agent also potentiates the stimulatory effect of carbachol on cyclic GMP synthesis. However, neither RO-201724/1 nor MIX alter basal secretion of 3H-labeled protein, nor do they affect the secretory response to carbachol used in either suboptimal or optimal concentrations. MIX as well does not alter the rate at which carbachol stimulates pancreatic enzyme release. The ability of carbachol to increase cyclic GMP synthesis is lost if extracellular calcium concentration is lowered to 0.05 mM; at this calcium concentration, however, the muscarinic agent still elicits a marked secretory effect. The dissociation between cyclic GMP synthesis and the secretory response suggests that the cyclic nucleotide does not play a major role in the stimulus--enzyme secretion coupling phenomenon of the exocrine pancreas.