Clostridioides difficile infection (CDI) is one of the main causes of morbidity associated with antibiotic use, producing both healthcare-associated infections and community infections. This study aims to describe the epidemiological characteristics, the clinical outcomes, previous antibiotic exposure, and other risk factors of hospitalized patients with CDI in a tertiary infectious disease hospital in Bucharest, Romania. We performed a descriptive analysis based on four-year surveillance data, collected in a tertiary infectious disease hospital in Bucharest, Romania. The annual incidence of CDIs varied from 65.1 cases per 10,000 discharges in 2020 to 211.7 cases per 10,000 discharges in 2023, with a continuously ascending trend. Most of the cases were hospital-acquired cases. There was a high share of antibiotic consumption three months before admission (61.3%). Third-generation cephalosporins, β-lactams with inhibitor combination, and carbapenems were the most used antibiotics, with shares of 46.0%, 25.2%, and 18.6%, respectively. Hospitalization in the previous 12 months and contact with a confirmed CDI case were other frequent factors in the study group, the occurrences of which were recorded as 66.2% and 2.4%, respectively. The surveillance data identified that the annual trend in CDIs is very variable, suggesting the need for continuous and multiannual analysis.