Mongolian gerbils were infected with a human pathogenic Giardia lamblia strain and compared with sham-treated control animals 6 days after inoculation. Infection resulted in crypt hyperplasia associated with an increased enterocyte migration rate. Villus height was decreased in the duodenum, unchanged in the jejunum, and increased in the ileum of infected animals. Epithelial microvilli were markedly shortened, and brush border surface area decreased in the jejunum and ileum of infected animals. Thymidine kinase activity was increased in isolated duodenal villus enterocytes but did not differ in the jejunum and ileum. In vitro and in vivo experiments showed that the infection resulted in decreased jejunal glucose-stimulated electrolyte, water, and 3-O-methyl-d-glucose absorption, whereas in the ileum in vitro electrolyte and 3-O-methyl-d-glucose absorption was similar in infected and control animals. Thus, in the jejunum infection causes electrolyte, solute, and fluid malabsorption associated with decreased brush border surface area. The results indicate that the diarrhea associated with giardiasis is caused by malabsorption rather than active secretion.