Diarrhea and wasting are among the most debilitating and deadly manifestations of AIDS, yet only limited information is available regarding the etiology, clinical consequences, and immunologic effects of infection with diarrheal agents. Peruvian AIDS patients presenting with and without diarrhea were followed prospectively to examine the relations among diarrheal pathogens, clinical presentations, CD4 lymphocyte count, weight loss, and survival. Patients with chronic diarrhea had lower CD4 lymphocyte counts (P = .001) and lost more weight (P < .001). Weight loss and a decreased CD4 lymphocyte count were associated with increased mortality (P = .011 and P = .003, respectively). Mean CD4 lymphocyte count varied significantly by diarrheal agent. Clostridium difficile was the most prevalent pathogen and was associated with significantly increased mortality before and after adjustment for coinfection, length of follow-up, CD4 lymphocyte count, and weight loss (P = .006). C. difficile may be a more important and more prevalent etiologic agent in AIDS than previously recognized and may represent a preventable cause of death in patients with immunosuppression.