AbstractObjective:To assess the relative risk of hospital-onset Clostridioides difficile(HO-CDI) during each month of the early coronavirus disease 2019 (COVID-19) pandemic and to compare it with historical expectation based on patient characteristics.Design:This study used a retrospective cohort design. We collected secondary data from the institution’s electronic health record (EHR).Setting:The Ohio State University Wexner Medical Center, Ohio, a large tertiary healthcare system in the Midwest.Patients or participants:All adult patients admitted to the inpatient setting between January 2018 and May 2021 were eligible for the study. Prisoners, children, individuals presenting with Clostridioides difficileon admission, and patients with <4 days of inpatient stay were excluded from the study.Results:After controlling for patient characteristics, the observed numbers of HO-CDI cases were not significantly different than expected. However, during 3 months of the pandemic period, the observed numbers of cases were significantly different from what would be expected based on patient characteristics. Of these 3 months, 2 months had more cases than expected and 1 month had fewer.Conclusions:Variations in HO-CDI incidence seemed to trend with COVID-19 incidence but were not fully explained by our case mix. Other factors contributing to the variability in HO-CDI incidence beyond listed patient characteristics need to be explored.