OBJECTIVES: To determine the incremental economic burden associated with Clostridium-difficile associated diarrhea (CDAD) among patient sub-populations at elevated risk for recurrent CDAD: immunocompromised (IC), prior CDAD, concurrent antibiotic use (cABx), renally impaired (RI), inflammatory bowel disease (IBD), and age ≥ 65 years (elderly) patients. METHODS: CDAD cases hospitalized with a diagnosis of CDAD (ICD-9-CM: 008.45) having ≥12 months of prior health plan eligibility and ≥18 years of age between January 1, 2005 and October 31, 2010 were identified from the HealthCore Integrated Research Database (HIRDSM). CDAD cases within each sub-population were matched to hospitalized controls without CDAD diagnosis based on: age±10 years, gender, preceding/in-hospital comorbidities (cardiovascular, pulmonary, haematopoietic, and musculoskeletal) and use of antibiotics. Incremental hospital length of stay (LOS) and hospital costs were calculated between matched cases and controls using multivariate generalized linear models using a Gamma distribution. Covariates were determined from post-match univariate analysis of baseline characteristics for each sub-population. RESULTS: Post-match case-to-control ratios ranged from 1:1 to 1:3 for each sub-population (IC: n=3,586 cases; prior CDAD: n=933 cases; cABx: n=4,429 cases; RI: n=5,533 cases; IBD: n=1,206 cases; elderly: n=10,933 cases). Post-match comparisons of baseline characteristics indicated no significant (P>0.05) difference in targeted match criteria. Compared to controls in all sub-populations, CDAD cases had significantly greater (P<0.0001) hospital LOS (mean incremental days [95% C.I.]; IC: 8.4 [7.9-9.0]; prior CDAD: 2.9 [2.4-3.6]; cABx: 7.8 [7.4-8.3]; RI: 17.3 [16.4-18.3]; IBD: 3.3 [2.9-3.7]; elderly: 7.8[7.5-8.1]) and hospital costs (mean incremental USD [95% C.I.]; IC: $31.8K [28.5-35.5]; prior CDAD: 28.0K [19.7-40.0]; cABx: 36.3K [33.3-39.6]; RI: $115.6K [105.2-127.1]; IBD: $11.2K [9.3-13.4]; elderly: $43.2K [40.9-45.7]).  CONCLUSIONS: This study demonstrates the significant incremental economic burden associated with CDAD both within the hospital setting and from a payer perspective. CDAD patients in each sub-population incurred significantly greater hospital LOS and corresponding hospital costs relative to matched controls.