Autologous peripheral blood progenitor cell (PBPC) transplant recipients frequently receive multiple antibiotics for neutropenic fever in addition to high-dose chemotherapy. Although there are many possible causes for diarrhea in this population, empiric therapy for possible C. difficile colitis is common in some centers. This study sought to define the frequency of diarrhea and of a positive C. difficile toxin assay in PBPC transplant recipients. Data were collected on 80 patients enrolled in a randomized trial of two different antibiotic regimens during PBPC transplant. Data included the presence or absence of diarrhea, all microbiologic studies performed during the transplant admission, and all antimicrobials administered during the transplant admission. Of 80 patients enrolled, 61 (76.3%) developed diarrhea. Only 3/61 (4.9%) had a positive C. difficile toxin assay. A total of 122 C. difficile toxin assays were performed; for each positive C. difficile assay, 41 stool samples were analyzed. Twenty courses of oral metronidazole (18/20 empiric) and 10 courses of oral vancomycin (8/10 empiric) were given. A total of 25 of 61 patients with diarrhea (41%) received therapy for possible C. difficile. Diarrhea is common during autologous PBPC transplant but a positive C. difficile assay is uncommon. The practice of empiric therapy for C. difficile in this population in a non-outbreak setting should be re-evaluated. Bone Marrow Transplantation (2000) 25, 67-69.