OBJECTIVE Small intestinal mucosal ultrastructural abnormalities were reported in a limited number of patients with cholera in the 1970s. This study extends these observations by examining distal duodenal biopsy samples from 19 patients with cholera and 10 controls. METHODS Endoscopic biopsy samples obtained, usually during the first 24 hours of illness, were processed for electron microscopy. RESULTS Widening of intercellular spaces and alteration of apical junctional complexes were prominent in the villus epithelium, whereas blebbing of microvillus border and mitochondrial changes were more prominent in the crypt epithelium. The apical junctional and intercellular space changes were not altered by oral rehydration. Degranulation of argentaffin cells, mucosal mast cells, and eosinophils; increase in neutrophil polymorphs; and changes in the enteric nerve fibers and microvasculature were also present. The extent of the changes correlated with clinical severity. CONCLUSIONS The differential involvement of the villus and crypt suggests that factors responsible for secretion may act differentially on surface and crypt epithelium and that both regions may contribute to secretion. The contribution of the enteric nervous system, vasculature, argentaffin cells, mucosal mast cells, eosinophils, and neutrophils in the secretory process and in determining the severity of the clinical illness must be determined by further clinical studies.