The Centers for Disease Control and Prevention identifies Clostridioides difficile infection (CDI) as an urgent threat to people and health care systems. CDI leads to high health care utilizations and results in significantly reduced quality of life for patients. The high burden of disease is seen across all health care settings, outside of the hospital, in the community, and in younger people. Individuals with CDI transition from hospitals to long-term care facilities to the community, and management of these transitions can reduce the incidence of recurrence and rehospitalization. The most common cause of diarrhea occurring in a health care setting is Clostridioides difficile and is also the cause of antibiotic-associated colitis (L. C. McDonald, 2021). The infection results from a disruption in the microbial flora of the gastrointestinal tract, mostly after antibiotic use or other medications such as proton pump inhibitors (PPIs). As a result, infected individuals are colonized and shed the spores into the environment, exposing others-goals of treatment focus on reducing the exposure and individual susceptibility. Although the incidence of C. diff is stable, recurrence is increasing significantly, with severe complications also a concern. The increased incidence and potential for life-threatening conditions require reducing initial exposure, supporting prescribed treatment, and preventing recurrence. C. diff infection can be contracted in health care facilities and in the community. Case managers from nearly all practice settings may encounter patients with the infection. To avert the devastating complications of Clostridioides difficile infection, case managers play an essential role in the prevention of recurrence with education, advocacy of best practices, effective care coordination, and thorough transitions of care. Each recurrence of C. diff infection leaves the patient vulnerable to the potential for surgical intervention, sepsis, and death. Mitigating the risk for readmission and recurrence will enhance C. diff infection care, safety, and outcomes to improve a patient's health care journey and quality of life. Case managers need to take a primary role in the transition and care coordination processes, including patient and support system education, coordination of any postdischarge services, connection to providers, adherence support activities, and follow-up for improvement or changes in condition. Supportive adherence activities and prevention education can result in the avoidance of recurrence. Case managers are well-equipped to locate resources to assist those patients challenged with the cost of medications, inability to attend appointments, or access basic needs. Although not directly related to C. diff, these challenges contribute to recurrence and readmission. Mitigating risk for readmission and recurrence results in an improved quality of life.