The purposes of this research were to determine whether microsporidian infection is accompanied by structural alterations of the duodenal mucosa and to characterize the clinical and morphological evolution of intestinal microsporidiosis. In a previous systematic electron microscopic evaluation of mucosal biopsy specimens from patients with human immunodeficiency virus infection, we detected Enterocytozoon bieneusi in the duodenal tissue of 31 men. This report concerns a follow-up study of these 31 men, who underwent repeated clinical and laboratory evaluations, including repeated duodenal biopsies. Eighteen men had chronic diarrhea at enrollment and 13 had no diarrhea. The CD4+ cell counts (per mm3) ranged from 10 to 660 and were normal for three men. E. bieneusi infection was accompanied by a wide spectrum of histopathology of duodenal tissue; over a mean follow-up of 15 months, no consistent change in duodenal mucosal morphology was observed, and diarrhea did not invariably develop. These observations indicate that diarrhea and severe villus injury do not invariably accompany infection. Further studies are needed to determine the relationship between E. bieneusi infection and clinical illness.