OBJECTIVES: Clostridium difficile-associated diarrhea (CDAD) increases the risk of hospital mortality.  Factors associated with CDAD recurrence include renal impairment (RI), inflammatory bowel disease (IBD) and advanced age (≥65 y).  These factors may also affect mortality risk; how CDAD modifies their effect on mortality is unknown. This cohort study analyzed these effects among hospitalized patients with hospital-origin CDAD (HO-CDAD) and community-origin CDAD (CO-CDAD) vs. non-CDAD controls. METHODS: A retrospective analysis (4/2005-6/2011) of the Health Facts database (Cerner Corp., Kansas City, MO) identified hospitalized adult patients with a positive C. difficiletoxin collected ≥48 hours (HO-CDAD) or <48 hours (CO-CDAD) after admission.  Generalized estimating equation models measured the effects of HO- and CO-CDAD, risk factors (RI, IBD, age ≥65), and their interactions on hospital mortality.  RESULTS: 4,505 patients with HO-CDAD, 2,825 with CO-CDAD, and 276,486 controls were identified.  Unadjusted hospital mortality was 13.0% in HO-CDAD, 10.7% in CO-CDAD and 2.7% in controls.  There was no interaction with Age≥65 and CDAD: the odds were approximately doubled regardless of CDAD status.  However, the effect of RI on mortality in HO-CDAD was 1.35 times higher than in controls (interaction odds ratio [OR] =1.35; 95% CI, 1.01-1.79). Considering the interaction term, the overall OR of dying with RI and HO-CDAD was 1.48 (95% CI, 1.12-2.00). Among controls, IBD had no significant effect on mortality (OR = 0.77; 95% CI, 0.52-1.14).  The interaction term for CO-CDAD and IBD was 3.05 (95% CI, 1.20-7.79), for an overall OR for IBD with CO-CDAD = 2.36 (95% CI, 1.08-5.14). CONCLUSIONS: The effect of RI and IBD on mortality varies by CDAD status.  RI and IBD have a synergistic (multiplicative instead of additive) effect with CDAD on mortality; if patients develop CDAD, their risk of dying greatly increases vs. controls.