Using a histochemical peroxidase technique, under conditions that preferentially stain erythrocytes, we have shown changes in the microcirculation of villi of neonatal mice infected with murine rotavirus. Between 18 and 48 h postinfection (PI), throughout all areas of the small intestine there occurred, sequentially, a marked ischemia and atrophy of villi. By 72 h PI, villi had recovered their normal height and showed incipient hyperemic microcirculation. At 96 h PI, hyperemic microcirculation was most marked. Between 120 and 144 h PI, a second phase of villus atrophy occurred, which was more attenuated and confined to the upper and middle regions of the intestine. This phase was not accompanied by a wide-spread ischemia of villi: a minority of villi were short and ischemic but many appeared hyperemic. Recovery of villus microcirculation occurred at 168 h PI, which coincided with recovery from diarrhea. These changes in villus microcirculation are discussed in relation to the pathology and pathophysiology of rotavirus infection. We make two novel suggestions. First, the reduction in red cells flowing through villi in the early stages of the infection instigates hypoxia and hence atrophy of villi. The ensuing but ephemeral increase in rate of cell division, necessary for the reconstitution of villi, induces hypersecretion. Second, the increase in numbers of erythrocytes found in villi during their regrowth phase and throughout the remaining time course of the infection perturbs the countercurrent system, lowering the osmolality of the hyperosmotic zone located at villus tips, thereby impairing water absorption and prolonging diarrhea.