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In the United States, influenza causes approximately 36,000 deaths and over 200,000 hospitalizations each year with elderly most often affected. Clostridium difficile infection (CDI) is another major health care challenge and pressing public health issue associated with 14,000 deaths and over 335,000 hospitalizations annually. The use of antibiotics has been implicated in the development of CDI. This study's purpose was to test the relationship of seasonal influenza incidence and antiviral/antibiotic use in CDI development among hospitalized patients. Grounded in the epidemiologic wheel model of man-environment interactions, this retrospective observational study described and analyzed data from a proprietary, laboratory, and pharmacy-based system from a cohort of hospitals. The association between 147 patients with a diagnosis and/or positive test for influenza, the independent variables of delivery of antivirals/antibiotics (n = 130) during the patient's hospitalization, and the dependent variable of positive test or diagnosis of CDI (n = 17) was tested using multiple logistic regressions. The study results did not prove to be significant for the 3 research questions, suggesting no impact of antiviral use (R2 = .05, p = .336), antibiotic use (R2 = .05, p = .290), or antiviral and/or antibiotic use (R2 = .04, p = .382) on development of CDI within 60 days of discharge. However, findings indicated that recommended antiviral medication was inconsistently administered to influenza positive patients and that inappropriate prescribing patterns for antimicrobial agents coincided with seasonal influenza. Implications for positive social change include confirming the importance of antibiotic stewardship as an essential aspect of quality healthcare.