These results highlight the high incidence of C. difficile infection in a subset of cancer patients at our institution. Although most patients presented with mild-moderate disease, severity of C. difficile infection in cancer patients may be underestimated due to the frequent presence of neutropenia. This study is the first analysis conducted, which directly compares outcomes of C. difficile infection after therapy with metronidazole, vancomycin, or combination therapy exclusively in patients with hematologic malignancies, including those undergoing hematopoietic stem cell transplant for a hematologic condition. We found no difference in treatment outcomes among metronidazole, vancomycin, or combination therapy. The recommendation from the literature to use metronidazole as the initial drug of choice for mild-moderate C. difficile infection is a reasonable option, although the rate of cure is low. This study highlights the critical need for better treatment options, due to suboptimal response rates to current therapy. Larger scale studies are needed to better understand the epidemiology and management of C. difficile infection in this patient population.