OBJECTIVE:To evaluate the National Health Safety Network (NHSN) hospital-onset Clostridioides difficile infection (HO-CDI) standardized infection ratio (SIR) risk adjustment for general acute-care hospitals with large numbers of intensive care unit (ICU), oncology unit, and hematopoietic cell transplant (HCT) patients. DESIGN:Retrospective cohort study. SETTING:Eight tertiary-care referral general hospitals in California. METHODS:We used FY 2016 data and the published 2015 rebaseline NHSN HO-CDI SIR. We compared facility-wide inpatient HO-CDI events and SIRs, with and without ICU data, oncology and/or HCT unit data, and ICU bed adjustment. RESULTS:For these hospitals, the median unmodified HO-CDI SIR was 1.24 (interquartile range [IQR], 1.15-1.34); 7 hospitals qualified for the highest ICU bed adjustment; 1 hospital received the second highest ICU bed adjustment; and all had oncology-HCT units with no additional adjustment per the NHSN. Removal of ICU data and the ICU bed adjustment decreased HO-CDI events (median, -25%; IQR, -20% to -29%) but increased the SIR at all hospitals (median, 104%; IQR, 90%-105%). Removal of oncology-HCT unit data decreased HO-CDI events (median, -15%; IQR, -14% to -21%) and decreased the SIR at all hospitals (median, -8%; IQR, -4% to -11%). CONCLUSIONS:For tertiary-care referral hospitals with specialized ICUs and a large number of ICU beds, the ICU bed adjustor functions as a global adjustment in the SIR calculation, accounting for the increased complexity of patients in ICUs and non-ICUs at these facilities. However, the SIR decrease with removal of oncology and HCT unit data, even with the ICU bed adjustment, suggests that an additional adjustment should be considered for oncology and HCT units within general hospitals, perhaps similar to what is done for ICU beds in the current SIR.