Marked morphological and functional damage to the small intestine occurs during the graft versus host reaction (GVHR); the structural lesion is characterized by crypt hypertrophy and villus shortening. The purpose of this study was to determine whether the intestine is injured in the GVHR as an antigenic target of the grafted immunocompetent cells or as an innocent bystander to donor-host lymphoid interaction. Implants of fetal mouse small intestine from either C57BL/6 or (C57BL/6 × DBA/2)F1(BDF1) hybrid donors were placed under the kidney capsule of adult BDF, male mice. After 4 weeks, both groups were injected with parental C57BL/6 spleen cells, syngeneic BDF, spleen cells, or no cells. Two weeks after injection the mice were killed and the implants were removed for histological processing and measurement of villus height and crypt depth. The villus-crypt ratio in the BDF1 implants of mice receiving C57BL/6 cells was 1.32 ± 0.3 compared to 2.51 ± 0.4 in controls receiving either syngeneic BDF1 cells or no cells (P < 0.001). The villus-crypt ratio in the C57BL/6 implants of mice receiving C57BL/6 cells was 1.79 ± 0.4 compared to 2.48 ± 0.4 in the controls receiving either syngeneic BDF1 cells or no cells (P < 0.001). Because the latter implant is antigenically identical to the spleen cells eliciting the GVHR, we conclude that the small bowel is injured in the GVHR as an innocent bystander to cytotoxic donor-host lymphoid interaction. © 1977, The American Gastroenterological Association. All rights reserved.