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(1) Background: Clostridioides difficile (C. difficile) and SARS-CoV-2 coronavirus represent significant health threats. Our study focused on the impact of concurrent infections on patient outcomes against the backdrop of changes imposed by the pandemic. (2) Materials and methods. We performed a retrospective analysis and included patients diagnosed with CDI who were admitted in our hospital before and during the pandemic. We compared patient exposure to risk factors for CDI in both groups and patient negative outcomes: need for ICU care, prolonged hospitalization, organ failure, toxic megacolon, and death. (3) Results. Overall, 188 patients were included, of which 100 had CDI (the pre-pandemic group), and 88 patients presented both CDI and COVID-19 (the pandemic group). Patients in the pandemic group were significantly older, with a higher Charlson Comorbidity Index (CCI) and a greater exposure to antibiotics and corticosteroids, and were more likely to develop organ dysfunction, to require ICU care and have prolonged hospitalization. The severity of COVID-19, leukocytosis and increased D-dimer levels were indicators of poor prognosis in the pandemic group. Higher CCI scores and leukocytosis increased the risk for negative outcomes in CDI alone patients. (4) Conclusions. The study highlights the negative impact of associated infections on patient outcome. The severity of COVID-19 directly influences the prognosis of patients with concurrent infections [ABSTRACT FROM AUTHOR]