OBJECTIVE To assess the development and cause of malabsorption in rhesus macaques following experimental simian immunodeficiency virus (SIV) infection and to evaluate its impact on nutritional status. METHODS Clinical malabsorption tests and serial jejunal aspirates and biopsies were obtained from nine SIV-infected and three uninfected animals prior to infection and at 1, 2, 4, 8, 12, 24, 40 and 52 weeks postinoculation. METHODS Malabsorption was measured by sucrose breath hydrogen (H2) analysis and blood assay of D-xylose. Digestive enzyme activity was determined in jejunal mucosal homogenates. Bacterial and protozoal flora were determined in jejunal aspirates. Nutritional assessment was evaluated using specific blood micronutrient values. Cellular targets of SIV in the jejunum were determined by combined in situ hybridization and immunohistochemistry. RESULTS Eight out of nine SIV-infected monkeys, including asymptomatic animals, exhibited malabsorption by either increased breath H2 and/or decreased blood D-xylose. All animals that died of AIDS had diarrhea, D-xylose malabsorption and decreased sucrase activity. Significant changes in nutritional status were associated with malabsorption. Bacterial overgrowth was not considered to be a cause of malabsorption. Histopathological biopsy findings included dilated villus lacteals, excessive cellular debris, lymphoplasmocytic infiltrates and cytoplasmic vacuoles in crypt epithelial cells. SIV-infected T cells and macrophages were detected as early as 1 week postinoculation. CONCLUSIONS SIV-associated malabsorption can occur prior to clinical complications of disease. Severe intestinal complications are associated with malabsorption and malnutrition in the terminal stages of AIDS. The high proportion of macaques experiencing malabsorption without detectable pathogens, suggests an enteropathogenic role for SIV.