Clinical observation suggests that the natural history of intestinal cryptosporidiosis in patients with acquired immunodeficiency syndrome varies greatly. The relation between clinical, small-bowel functional, and nutritional status and the intestinal distribution of the organism was studied in 41 patients who had acquired immunodeficiency syndrome and cryptosporidiosis and who had undergone both proximal small-bowel and colonic biopsies. Two patterns of enteric cryptosporidiosis were identified: severe clinical disease with malabsorption in patients with cryptosporidia in proximal small-bowel biopsy specimens (61% of cases) and less severe clinical disease in patients with cryptosporidia only in the colon or stool (39% of cases). Patients with cryptosporidia in proximal small-bowel biopsy specimens had small-bowel crypt hyperplastic villous atrophy, lamina propria inflammatory infiltrates, poorer D-xylose absorption, greater weight loss, and shorter survival and more often needed intravenous hydration or hyperalimentation. Patients with cryptosporidia in the small-bowel villi only had less severe disease than those with cryptosporidia in the small-bowel crypts. In conclusion, the anatomic distribution of intestinal cryptosporidia in patients with acquired immunodeficiency syndrome varies, and this variation may explain differences in clinical course. Cryptosporidial infection of the proximal small bowel correlates with mucosal injury, malabsorption, dehydration, weight loss, and shortened survival.