The burden of Clostridioides difficile infection (CDI) in South Korea has been unclear due to the absence of a reliable identification algorithm and comprehensive surveillance system. This study aimed to examine CDI epidemiology from 2015 to 2021, focusing on incidence rates and healthcare utilization characteristics. A national retrospective cohort of CDI cases was established using Korean National Health Insurance claims data. CDI cases were identified through inpatient claims records of diagnosis codes, laboratory testing, and treatment for CDI. Total and annual CDI incidence rates per 100,000 person-years were calculated. The cohort was stratified by CDI diagnosis to assess differences in patient demographics, healthcare institution characteristics, and healthcare utilization. Drug utilization for CDI treatment was evaluated within each stratified cohort. The overall annual CDI incidence has been increased from 151.0/100,000 person-years in 2015 to 371.0/100,000 person-years in 2021. The undiagnosed group had longer hospital stays, higher costs, surgery rates, and in-hospital death rates compared to diagnosed cases. Significant differences were observed in the management of diagnosed and undiagnosed CDI, particularly in terms of patient characteristics and healthcare utilization, including costs.