A quantitative light microscopic morphometric analysis of lysozyme- and IgA-containing Paneth cells within the ileal mucosa of physiologically manipulated and control (sham operation) animals was performed. The experimental groups of rats included animals raised in a gnotobiotic environment (microbial reduction) and animals with ileal self-filling blind (microbial proliferation) and Thiry-Vella (intestinal discontinuity) loops. The unlabeled antibody enzyme immunohistochemical localization technique was employed for the identification of intracellular lysozyme and IgA. Component quantitation was performed by use of a micrometer component quantitator. Marked Paneth cell hyperplasia was noted in association with gnotobiosis and with the Thiry-Vella fistula. This observation quantitatively confirms previous subjective impressions of increased Paneth cell differentiation in association with those physiologic states. Since the neurovascular component of the Thiry-Vella fistula is intact, the normal intraluminal succus entericus would appear to be involved in modulation of Paneth cell differentiation. The recognition of Paneth cell hyperplasia in association with the Thiry-Vella fistula suggests that this may be a useful experimental model for an evaluation of the life cycle and functional characteristics of this cell population. The results also revealed that no significant change in the volume percentage of Paneth cells and a decreased volume percentage of Paneth cells containing IgA occurred in association with the self-filling blind loop. A decreased volume percentage of IgA-containing immunocytes in association with the blind loop has previously been reported. The data are most consistent with the interpretation that the Paneth cell and immunocyte response to antigenic stimulation are interrelated and that the Paneth cell population has a restricted latitude of response to microbial proliferation.