Clostridium difficile infection usually results from long-term and irregular antibiotic intake. The high-risk individuals for this infection include the patients undergoing chemotherapy due to malignancy, immunocompromised patients, and hospitalized patients receiving broad-spectrum antibiotics. The most common clinical manifestation of Clostridium difficile infection is diarrhea. However, pleural effusion and ascites have rarely been observed. As mentioned, these manifestations can be developed in a patient being treated with broad-spectrum antibiotics. Therefore, the present study reports a rare case of Clostridium difficile infection manifesting with these rare manifestations who was a 78-year-old female patient with a history of COVID-19, orthopedic surgery, and antibiotic treatment with cefixime and gentamicin.