The seasonal activity of pepsinogen secretion in the Rana catesbeiana was studied by use of peptic gland bearing esophageal mucosa mounted in a perfused double chamber. The amount of the basal pepsinogen secretion during hibernation (winter) and breeding (spring) periods was approximately 25 and 55% of basal secretion during the active (summer) period. The circumannual variation of basal secretion was highly correlated (r = 0.88, n = 37) with the pepsinogen content of the mucosa. The fractional rate of basal secretion (approximately 2% of content per hour) remained essentially constant, and pepsinogen as a fraction of total protein remained at between 20 and 25%. The results indicate that the decrease in absolute basal secretion from frog peptic glands during winter is a consequence of decreased content and hence synthesis of protein, including pepsinogen, by the mucosa. In addition, stimulated secretory responses to both bethanechol and bombesin, as a multiple of basal rate, were reduced during both hibernation and breeding periods, whereas the response to isoproterenol was entirely abolished during the hibernation period. By contrast, the secretory response to isobutylmethylxanthine remained constant (approximately 200% of basal) through all seasons, suggesting that mechanisms responsible for enzyme translocation and secretion remained intact. Reduced basal and secretagogue-stimulated secretion during hibernation and breeding seasons is thus likely due to a combination of reduced protein synthesis and decreased number or function of agonist receptors in peptic cells of the frog.