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Background.Clostridium difficile infection (CDI) has increased in frequency and severity over the past decade. An understanding of the modifiable risk factors for disease severity has considerable clinical applicability.Methods. We performed a retrospective case review of 485 cases in patients aged 1–99 years at the Naval Medical Center San Diego from November 2004 through December 2008. We compared potential risk factors for association with complications (megacolon, surgery, intensive care unit stay, and death) or mortality alone with use of univariable and multivariable logistic regression modeling.Results. Forty-seven patients (9.8%) developed ≥1 complication, and 23 (4.7%) died. We found independent associations between complications and acid suppression (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.2–4.79), admission for CDI (OR, 4.14; 95% CI, 2.17–7.92), older age (≥80 years; OR, 3.14; 95% CI, 1.46–6.73), and corticosteroid use (OR, 2.09; 95% CI, 1.01–4.35). Age ≥80 years (OR, 5.51; 95% CI, 2.25–13.49) and acid suppression (OR, 4.74; 95% CI, 1.57–14.37) were associated with increased odds of death.Conclusions. Data published elsewhere have suggested that acid suppression therapy is a risk factor for CDI acquisition and relapse. These findings suggest an additional role in increased severity of disease, including mortality, and merit further study.