Background <p><i>Clostridioides difficile</i> infection (CDI) is one of the most prevalent hospital-acquired infections, causing high morbidity and mortality. While incidence rates have recently increased in many countries, its epidemiology after the COVID-19 pandemic has yet to be determined. This study analyzes the characteristics and evolution of CDI in hospitalized patients in Spain.</p> Methods <p>This retrospective observational study was based on coded hospital discharge reports between 2016 and 2022 using the national hospital discharge database (MBDS), ICD-10 code A04.7. The variables analyzed were sex, age, comorbidities, diagnoses at discharge, procedures, overall severity, whether CDI was coded as a primary or secondary diagnosis, admission to the intensive care unit (ICU), length of stay, and in-hospital all-cause mortality.</p> Results <p>There were 66,864 CDI cases (52.8% in women), affecting 0.22% of admissions. The mean age (70.4 years) and mean Charlson comorbidity index (2.49) increased over time. The overall rate per 1,000 admissions and the population-based mean incidence rate almost doubled between 2016 and 2022. Most cases (61.2%) were secondary cases. These patients were younger, more frequently admitted to the ICU, had higher comorbidity, more colectomies, and longer hospital stays. Overall mortality was 11.3%, significantly higher in secondary CDI, and it peaked in 2020. In-hospital all-cause mortality was higher in older patients (OR 1.04), those with more comorbidities (OR 1.14), those in the ICU (OR 28.54) and those with moderate (OR 1.54), high (OR 3.77), or extreme overall severity (OR 10.39).</p> Conclusions <p>The CDI incidence has increased in Spain. Age, comorbidities, overall severity, and admission to the ICU predicted poor outcomes in hospitalized patients with CDI. Preventive measures are warranted to decrease the disease burden.</p> Clinical trial <p>Not applicable.</p>