Background: Clostridium difficile infection (CDI) is one of the most important affecting patients immunocompromised by autologous stem cell transplantation (ASCT), and can be associated with increased morbidity and length of stay. One precipitating factor for index CDI cases in the ASCT population is heavy antibiotic exposure, which often includes prophylaxis. A retrospective review identified 11 cases of CDI (17%) in the 30-day period following ASCT performed at the University of Virginia Medical Center (UVAMC) between about June 2016 and July 2017. Various institutional and multicenter studies have reported incidence rates in this population ranging from less than 5% to more than 10%. Methods: To decrease CDI rate, a multidisciplinary team comprised of oncology and infectious diseases physicians, pharmacists, and nurses was formed. The group used quality improvement principles to identify and target areas of greatest significance. A first PDSA cycle was conducted between approximately July 2017 and June 2018, during which time administration of standard-of-care ciprofloxacin prophylaxis between T+0 and count recovery was suspended. A second PDSA cycle was executed between approximately May 2018 and July 2019, incorporating UV light equipment into existing post-discharge cleaning practices. Data were analyzed using process control charts with 3-sigma limits for ASCT length-of-stay (LOS) and 30-day post-transplant CDI incidence. Results: Suspension of prophylactic antibiotics did not have a significant effect on CDI incidence in our first PDSA cycle. In our second improvement cycle, most of which elapsed after prophylactic ciprofloxacin had been re-implemented, CDI incidence was almost halved, from 17 to 9%. A numerical decreased in LOS was observed in each subsequent PDSA cycle. Conclusions: Our multidisciplinary team applied quality improvement methods to drive a clinically significant reduction in the 30-day CDI incidence after ASCT at UVAMC. This outcome should be associated with an improved patient experience. Future PDSA cycles are scheduled and may include other cancer patients, beyond those receiving stem cell transplantation.