Background Preventing the transmission of Clostridium difficile infection (CDI) over the continuum of care presents an important challenge for infection control. Methods A prospective case-control study was conducted on patients admitted with CDI to a tertiary care hospital in Detroit between August 2012 and September 2013. Patients were then followed for 1 year by telephone interviews and the hospital administrative database. Cases, patients with interfacility transfers (IFTs), were patients admitted to our facility from another health care facility and discharged to long-term care (LTC) facilities. Controls were patients admitted from and discharged to home. Results There were 143 patients included in the study. Thirty-six (30%) cases were compared with 84 (70%) controls. Independent risk factors of CDI patients with IFTs (compared with CDI patients without IFTs) included Charlson Comorbidity Index score ≥6 (odds ratio [OR], 5.30; P = .016) and hospital-acquired CDI (OR, 4.92; P = .023). Patients with IFTs were more likely to be readmitted within 90 days of discharge than patients without IFTs (OR, 2.24; P = .046). One-year mortality rate was significantly higher among patients with IFTs than among patients without IFTs (OR, 4.33; P = .01). Conclusions With the growing number of alternate health care centers, it is highly critical to establish better collaboration between acute care and LTC facilities to tackle the increasing burden of CDI across the health care system.