BACKGROUND: Clostridioides difficile infections (CDIs) have been identified as a major health concern due to the high morbidity, mortality, and cost of treatment. The aim of this study was to review the extant literature and identify the various patient-related, medication-related, and organizational risk factors associated with developing hospital-acquired CDIs in adult patients in the United States. METHODS: A systematic review of four (4) online databases, including Scopus, PubMed, CINAHL, and Cochrane Library, was conducted to identify empirical studies published from 2007 to 2017 pertaining to risk factors of developing hospital-acquired CDIs. FINDINGS: Thirty-eight studies (38) were included in the review. Various patient-level and medication-related risk factors were identified including advanced patient age, comorbidities, length of hospital stay, previous hospitalizations, use of probiotic medications and proton pump inhibitors. The review also identified organizational factors such as room size, academic affiliation, and geographic location to be significantly associated with hospital-acquired CDIs. CONCLUSION: Validation of the factors associated with high risk of developing hospital-acquired CDIs identified in this review can aid in the development of risk prediction models to identify patients who are at a higher risk of developing CDIs and developing quality improvement interventions that might improve patient outcomes by minimizing risk of infection.