Although the bulk of the literature implies that most of the radiation-induced effects on small intestine are related to epithelial damage, previous work has indicated that there are structural changes in the neuromuscular component of the wall. The short timescale of changes in villous shape produced by hyperthermia but similar to those seen after radiation, also supports the claim that there is a neuromuscular contribution involved. A preliminary report showed that the radiation-induced changes in the small intestine could be simulated by the administration of reserpine, a drug chosen for its effects on the neuromuscular component of the mucosal wall. A system of villous scoring indicated that the overall effects of the two regimes were approximately equivalent in terms of the changes produced in the shape of the villi. The current paper describes the results of experiments to compare the two regimes over the time scale 1 h to 3 days. The time points were chosen to include likely maximum damage caused by reserpine (18 h after treatment) and radiation (3 days after treatment). Mice were irradiated with 15 Gy gamma-rays from a 60Co source or treated with reserpine (1 mg/kg and 16 mg/kg). Scanning electron microscopy showed some changes in the duodenal mucosal topography of some control groups which may be related to the stress of treatment and are in keeping with previous findings. However, the changes seen in treated groups were greater than those found in the corresponding control samples. The overall villous changes were plotted using a grid score method, which showed that both radiation and reserpine treatment altered the villous morphology in a similar way. Light microscopy and transmission electron microscopy showed that smooth muscle damage was associated with the villous collapse. The work indicates that the intestinal wall can be damaged by many agents and that greater understanding of radiation-induced damage can be gained by comparing it with that produced in other ways.