Abstract: Clostridioides difficile infection is a critical public health concern in nosocomial infection control and epidemiology research. Immunocompromised population is at high risk due to immunosuppression, frequent healthcare exposure, and antibiotic use. This paper summarizes the epidemiological characteristics of C. difficile infection, risk factors and prevention strategies in four key groups: ICU patients, HIV-infected individuals, tuberculosis patients, and solid organ transplant recipients. The analysis indicated that the incidence of C. difficile infection was significantly higher in these groups than in general population. The infection was associated with progressed immunosuppression, broad-spectrum antibiotic use, prolonged hospitalization, and invasive procedures, suggesting the need for the stratified risk surveillance in immunocompromised population, strengthened antibiotic use management, improved nosocomial infection control, and differentiated prevention strategies. It is necessary to conduct multi-center prospective studies integrating immunological and microbiome indicators to develop risk prediction models for the precise prevention and control of C. difficile infection.