OBJECTIVE: Asymptomatic patients colonized with toxigenic METHODS: This was a nested case-control study at an academic medical center including adult patients colonized with toxigenic RESULTS: Of 2,150 colonized patients, 109 developed HO-CDI, with an incidence of 5.1%. After exclusions, 321 patients (69 with HO-CDI) were included, with an estimated incidence of 4.2%. Risk factors included cirrhosis (aHR 1.94), ICU admission (aHR 1.76), malignancy (aHR 1.88), and hospitalization within six months (aHR 1.6). Prior antibiotic exposure in the past three months (aHR 2.14) and receipt of at-risk antibiotics were also identified as potential risk factors (aHR 2.17). CONCLUSIONS: Progression to HO-CDI among colonized patients was not uncommon. This study highlights key risk factors associated with progression, underscoring the importance of enhanced monitoring and prevention efforts tailored to high-risk populations to mitigate HO-CDI.