Of 427 human immunodeficiency virus-seropositive patients admitted to the Robert Wood Johnson University Hospital from January 1986 through August 1992, seven had Clostridium difficile enteric infection documented by the presence of cytotoxin B in the stool, without other enteric infection. All seven patients had AIDS, and all had recently received antibiotics. These patients had a severe clinical presentation of C. difficile infection. All patients had profound watery diarrhea, with a mean of 20 +/- 14 (SD) bowel movements per day. Four had fever > 38.5 degrees C, and another had hypothermia. Three patients had borderline hypotension, and another was orthostatic. The mean pulse was 119 +/- 26 (SD) beats/min. Five patients had abdominal pain and tenderness. Two had occult blood in the stool. Four had metabolic derangements such as hyponatremia, hypokalemia, or prerenal azotemia. Three of four patients undergoing abdominal roentgenography had radiographic findings consistent with severe colitis of colonic dilation, mural thumbprinting, or mural thickening. Sigmoidoscopic findings ranged from diffuse erythema to prominent pseudomembranes. During a mean interval of 14.3 +/- 6.2 (SD) days before institution of specific antibiotic therapy, the diarrhea spontaneously resolved in only one of the seven patients. In the others, the diarrhea resolved on average 7.3 +/- 4.0 (SD) days after instituting antibiotic therapy. During a mean follow-up of 4.4 +/- 6.3 (SD) months, only two patients redeveloped diarrhea. Both patients had recurrent C. difficile colitis; the symptoms again rapidly resolved after repeat antibiotic therapy. We conclude that in patients with AIDS C. difficile may present as a severe enteric infection with profound diarrhea due to immunosuppression, that the diarrhea may be prolonged and not remit spontaneously, and that the diarrhea usually rapidly resolves with specific antibiotic therapy.