OBJECTIVE:Hospital-onset Clostridium difficile-associated diarrhea (HO-CDAD) has been associated with longer length of stay (LOS) and higher hospital costs among patients in general. The burden of HO-CDAD is unknown among patients who may be at particular risk of poor outcomes: older patients, those with complex or chronic conditions (renal disease, cancer, inflammatory bowel disease [IBD]), and those with concomitant antibiotic (CAbx) use during treatment for CDAD. RESEARCH DESIGN AND METHODS:A retrospective analysis (2005-2011) of the Health Facts® database (Cerner Corp., Kansas City, MO) containing comprehensive clinical records from 186 US hospitals identified hospitalized adult patients with HO-CDAD based on a positive C. difficile toxin collected >48 h after admission. Control patients were required to have total hospital LOS ≥2 days. Separate logistic regression models to estimate propensities were developed for each study group, with HO-CDAD vs controls as the outcome. Differences in LOS and costs were calculated between cases and controls for each group. RESULTS:A total of 4521 patients with HO-CDAD were identified. Mean age was 70 years, 54% were female, and 13% died. After matching, LOS was significantly greater among HO-CDAD patients (vs controls) in each group except IBD. The significant difference in LOS ranged from 3.0 (95% CI = 1.4-4.6) additional days in older patients to 7.8 (95% CI = 5.7-9.9) days in patients with CAbx exposure. HO-CDAD was associated with significantly higher costs among older patients (p < 0.001) and among those with renal impairment (p = 0.012) or CAbx use (p < 0.001). LIMITATIONS:Missing cost data and potential misclassification of colonized patients as infected. CONCLUSIONS:Renal impairment, advanced age, cancer, and CAbx use are associated with significantly longer LOS among HO-CDAD patients, with CAbx users being the most resource intensive. Early identification and aggressive treatment of HO-CDAD in these groups may be warranted.