Study objective: To determine the frequency of pathogenic gastrointestinal microorganisms in patients with the acquired immunodeficiency syndrome (AIDS) and diarrhea, and to determine if treatment for identifiable microorganisms improves symptoms. Design: Prospective, consecutive sample study. Setting: Referral-based clinic and wards, National Institutes of Health. Patients: Twenty of twenty-two consecutive homosexual males with AIDS and diarrhea, and 10 homosexual males with AIDS without diarrhea. Interventions: All patients had a complete physical examination; serial stool examinations for viral, bacterial, fungal, and protozoan pathogens; and esophagogastroduodenoscopy and colonoscopy to obtain duodenal fluid and mucosal tissue to analyze for enteric pathogens or histopathology. Patients with diarrhea had a malabsorption evaluation. Patients with treatable pathogenic microorganisms received standard antimicrobial therapy. Measurements and main results: The 20 patients with AIDS and diarrrhea had greater weight loss, lower mean numbers of helper-inducer (OKT4) lymphocytes, and a higher incidence of extraintestinal opportunistic infections than the 10 patients without diarrhea. One or more enteric pathogen was identified in 17 of 20 patients (85%; 95% confidence interval [CI], 65% to 96%) with diarrhea. Only 1 patient without diarrhea was infected with an enteric pathogen. Nineteen of twenty patients with diarrhea and all 10 patients without diarrhea had chronic inflammatory changes in their intestinal biopsy specimens. Sixteen patients with identifiable enteric pathogens and diarrhea were treated; 11 (69%; 95% CI, 43% to 87%) showed microbiologic, histologic, or clinical improvement. Conclusions: Thorough diagnostic evaluation can lead to the identification of enteric pathogens in a high percentage of patients with AIDS and diarrhea. Specific therapy can lead to symptomatic improvement.