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Study Objectives The primary objective was to determine the impact of hematologic malignancies and/or conditioning regimens on the risk of developing Clostridium difficile infection (CDI) in patients undergoing hematopoietic stem cell transplantation (HSCT). Secondary objectives were to determine if traditional CDI risk factors applied to patients undergoing HSCT and to determine the presence of CDI markers of severity of illness among this patient population. Design Single-center retrospective case-control study. Setting Quaternary care academic medical center. Patients A total of 105 patients who underwent HSCT between December 2009 and December 2014; of these patients, 35 developed an initial episode of CDI (HSCT/CDI group [cases]), and 70 did not (controls). Controls were matched in a 2:1 ratio to cases based on age (± 10 yrs) and date of HSCT (± 6 mo). Measurements and Main Results Baseline characteristics of the two groups were well balanced regarding age, sex, race, ethnicity, and type of HSCT. No significant differences in conditioning regimen, hematologic malignancy, total body irradiation received for HSCT, use of antibiotics within 60 days of HSCT, or use of prophylactic antibiotics after HSCT were noted between the two groups. Patients in the control group were 10.57 (95% confidence interval 1.24-492.75) more likely to have received corticosteroids prior to HSCT than patients in the HSCT/CDI group (p=0.01). Use of proton pump inhibitors at the time of HSCT was greater among the control group than among patients in the HSCT/CDI group (97% vs 86%, p=0.048). No significant difference in mortality was noted between the groups at 3, 6, and 12 months after HSCT. Metronidazole was frequently prescribed for patients in the HSCT/CDI group (34 patients [97%]). Severe CDI was not common among patients within the HSCT/CDI group (13 patients [37%]); vancomycin was infrequently prescribed for these patients ([31%] 4/13 patients). Conclusion Hematologic malignancies and a conditioning regimen administered for HSCT were not significant risk factors for the development of CDI after HSCT. Use of corticosteroids prior to HSCT and use of proton pump inhibitors at the time of HSCT were associated with a significantly decreased risk of CDI. [ABSTRACT FROM AUTHOR]