We have used measurements of intestinal epithelial cell kinetics and counts of intraepithelial lymphocytes and mucosal mast cells to measure small intestinal mucosal changes during the proliferative and recovery phases of graft-vs.-host reaction in neonatal mice. Unirradiated (CBA x BALB/c)F1 mice were injected with parental spleen cells or with culture medium at 6-8 days of age, and followed up for 9 wk thereafter. The spleen index was used as a measure of the graft-vs.-host reaction, a stathmokinetic technique with microdissection was used to measure villus and crypt lengths and crypt cell production rate, and intraepithelial lymphocytes and mucosal mast cells were counted in histologic sections. Intraepithelial lymphocyte count rose within 24 h of induction of the graft-vs.-host reaction and increases in crypt length and in crypt cell production rate occurred within 3 days. These indices exactly parallel the spleen index during the proliferative phase of the graft-vs.-host reaction and the changes occurred in the absence of any villus damage. Mucosal mast cell numbers also increased, but the rise was delayed and sustained when compared with other mucosal changes. These results show that measurements of mucosal architecture and intraepithelial lymphocyte counts can be used to quantify mucosal cell-mediated immune reactions. In addition, this study provides further evidence to support our hypothesis that the mechanism of these changes is due to a delayed-type hypersensitivity reaction in the intestinal mucosa rather than to the action of cytotoxic T lymphocytes.