We have compared the diameters of zymogen granules in the exocrine pancreas of fasted or stimulated rats. The average granule diameter was 0.73 microns +/- 0.18 SD (sample size, 1460) in fasted animals and significantly reduced to 0.68 microns +/- 0.17 SD (sample size, 860) after 120 min and two intraperitoneal injections of urecholine. Reduction of granule size was attributable to the preferential discharge of large size granules. The range between first and third quartiles of the distribution curve was identical in the two groups at 0.24 microns. There was no significant increase in the proportion of granules smaller than 0.40 microns after urecholine stimulation. A third group of animals was "hyperstimulated" by an infusion of a mixture of caerulein, secretin, and urecholine. After 210 min, the average granule diameter was reduced to 0.43 microns +/- 0.14 SD (sample size, 786). The range between first and third quartiles of the distribution curve was 0.16 microns. In this group, 43.5% of the granules was smaller than 0.40 microns. Granule size reduction was accompanied by the appearance of numerous pleiomorphic condensing vacuoles. The present results strongly support the views that secretagogues cause the preferential release of large size granules and favor the formation of small size granules.