Clostridium perfringens causes pyogenic liver abscesses, which are rare but rapidly fatal infections. These abscesses often occur in patients with immunodeficiency due to malignancy, liver cirrhosis, diabetes mellitus, or organ transplantation. The identification of gram-positive bacilli in septicemia, the presence of gas-forming liver damage and intravascular hemolysis are manifestations of Clostridium perfringens infection. Clostridioides toxin A hydrolyzes phospholipids in erythrocyte membranes, causing spherocytosis and subsequent intravascular hemolysis, resulting in rapid deterioration and a high mortality rate. A 62-year-old man with recurrent hepatocellular carcinoma complained of a high fever and abdominal pain one day after microwave ablation. Abdominal computed tomography revealed gas-containing lesions in the liver. His condition was complicated with massive hemolysis. Laboratory examinations revealed low hemoglobin, high serum lactate dehydrogenase, and elevated indirect bilirubin levels, suggesting massive intravascular hemolysis. Although aggressive treatment was applied, he died within 16 hours after onset of the infection. After the patient died, a blood culture indicated Clostridium perfringens positivity. Clostridium perfringens-induced septicemia with massive hemolysis is rare but rapidly leads to a severe prognosis. It is important to identify Clostridium perfringens infection early and initiate effective treatment, especially abscess aspiration, which should be performed as soon as possible.