The aim of this study was to investigate the differences of Clostridioides difficile infection (CDI) during the COVID-19 pandemic compared to the pre-COVID-19 era. CDI patients treated at the Clinic for Infectious Diseases, Clinical Center of Vojvodina, Serbia during 2017–2019 (n = 304) were compared with COVID-19/CDI patients treated in period September 2021–September 2022 (n = 387). Groups were compared by age, gender, comorbidities, previous medications, laboratory findings, and outcome within 30 days. In the CDI/COVID-19 group, we found: greater percentage of males 59.8% vs. 42.6% (p ≤ 0.001), older age 72.8 ± 9.4 vs. 65.6 ± 11.7 (p ≤ 0.001), higher Charlson comorbidity score (CCS) (3.06 ± 1.54 vs. 2.33 ± 1.34 (p ≤ 0.001), greater percentage of chronic renal failure (33.9% vs. 23.4% (p = 0.003), malignances (24.3% vs. 13.5% (p ≤ 0.001), chronic obstructive pulmonary disease (22.7% vs. 15.5% (p = 0.017), higher usage of macrolide (38.5% vs. 8.6% (p ≤ 0.001), greater percentage of patients with hypoalbuminemia ≤25 g/L (19.6% vs. 12.2% (p ≤ 0.001), lower percentage of patients with elevated creatinine (≥200 mmol/L) (31.5% vs. 43.8%) (p = 0.002), and greater percentage of lethal outcome 29.5% vs. 6.6% (p ≤ 0.001). In the prediction of lethal outcome multivariate regression analysis extracted as an independent predictor, only higher CRP values in the non-COVID-19 group and in the COVID-19 group: older age (p ≤ 0.001), CCS (p = 0.019) and CRP (p = 0.015). COVID-19 changes the disease course of CDI and should be taken into consideration when managing those patients.

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We believe that this good result in treatment outcome was the consequence of proper selection of patients based primarily on regulations of Republic of Serbia on the necessity of abstinence from the use of alcohol and psychoactive substances at least one year before starting antiviral therapy.