Evaluations of oral vancomycin prophylaxis (OVP) against Clostridioides difficile have been reported in stem cell transplant populations with short follow-up periods. The longest known duration of standardized follow-up post-OVP is 90 days within an allogeneic stem cell transplant population. In 2017, we implemented OVP 125 mg twice daily in autologous stem cell transplant (ASCT) recipients beginning the day of admission and continued until the day of discharge. Patients who received an ASCT within our institution between 1 January 2012 and 31 December 2021 were included and separated into 2 groups based on the receipt of OVP. The primary study aim was to measure the incidence of C difficile infection (CDI) during the ASCT admission. A secondary aim was to evaluate for delayed CDI 180 days post-discharge. Other factors evaluated were prior history of CDI, use of systemic antimicrobials, and length of stay. Overall, 254 patients were evaluated and 58% received OVP, predominantly as primary prophylaxis (95%). Of the 18 patients who developed in-hospital CDI, 6 were in the OVP group versus 12 in the non-OVP cohort (4% vs 11%, P = .03). In the 180-day follow-up period, OVP use did not increase risk of developing CDI after discontinuation while in-hospital length of stay was identified as a significant factor. The use of OVP significantly reduced the incidence of CDI during the in-hospital ASCT course without increasing CDI post-OVP use. These encouraging results should promote further research into the use of OVP in ASCT.