Clostridium perfringens (CP) is an anaerobic bacterium that rarely causes fatal massive intravascular hemolysis (MIH) with high mortality in patients with hematological diseases. A retrospective study analyzed 23 cases, of which 60.8% were men with an average age of 45.87 ± 17.94 years. All patients had fever, 69.5% hematuria, 78.2% shock, and 60.8% altered mental status (AMS). The overall mortality rate was 73.9%, with a median survival of 13.5 (6–24) hours for those who died. AMS was shown to be an independent risk factor for mortality (OR = 14.03, 95% CI: 1.19–165.08, p = 0.036). The pathogenic cascade is caused by the synergistic action of α-toxin and θ-toxin, leading to hemolysis and organ damage. Immediate antibiotic therapy (penicillin with clindamycin) along with supportive intensive care is recommended.