At endoscopy, a 30-year-old man with acquired immune deficiency syndrome (AIDS), Kaposi's sarcoma, diarrhea, and unexplained malabsorption showed erythematous macular duodenal lesions consistent with Whipple's disease by histology and electron microscopy. Symptoms did not respond to tetracycline. Subsequent cultures revealed systemic Mycobacterium avium (M. avium) infection. Tissue from this patient, from patients with Whipple's disease and from a macaque with M. avium were compared. All contained PAS-positive macrophages but M. avium could be distinguished by positive acid-fast stains and a difference in pattern of indirect immunofluorescence staining with bacterial typing antisera. PAS-positive macrophages in the intestinal lamina propria are no longer pathognomonic of Whipple's disease. Ultrastructural and histological similarities between Whipple's disease and M. avium infection suggest that both are manifestations of immune deficits limiting macrophage destruction of particular bacteria after phagocytosis. M. avium must be considered in the differential diagnosis of diarrhea in patients with AIDS and other immunosuppressed conditions.