Human calicivirus (HuCV), a common cause of mild gastroenteritis in the general population, produces a prolonged diarrheal illness in pediatric recipients of small intestinal transplant (IT). By use of reverse-transcription polymerase chain reaction to detect the viral RNA polymerase gene in stool and tissue from gastrointestinal biopsies, 5 pediatric IT recipients with high-volume diarrhea were diagnosed with HuCV enteritis. Histopathologic findings of biopsies obtained at different gastrointestinal sites were studied retrospectively to identify characteristic features of HuCV enteritis and to distinguish these changes from rejection. Controls were 8 pediatric IT recipients with high-volume diarrhea but negative HuCV reverse-transcription polymerase chain reaction assays during the same time period. All HuCV biopsies showed increased mononuclear infiltrates in the lamina propria and villous blunting. Reactive disarray of surface epithelial cells and increased apoptosis in the surface epithelium and superficial lamina propria were characteristic features (in 4/5 patients). Increased glandular apoptosis was also present in 3/5 patients. Findings were more pronounced in jejunal allograft than ileal allograft, and were present in both graft and native bowel. In comparison with the control group, the architectural changes, surface epithelial reactive changes, and superficial apoptosis were characteristic of HuCV enteritis, while the presence of glandular apoptosis was a feature shared with cases of mild acute cellular rejection HuCV may cause severe allograft dysfunction after pediatric IT. Calicivirus infection has clinical and histological features that overlap with allograft rejection. Knowledge of the characteristic histologic features of HuCV enteritis aids in differential diagnosis.