Rhesus (Rh) mediated hemolytic transfusion reactions (HTR) are usually immunoglobulin G mediated and delayed onset. Rh antibodies being the cause of acute HTR (AHTR) and intravascular hemolysis are still under debate. We report here a case of a 53-year-old male who developed AHTR due to "anti-c" antibodies within 3 h of blood transfusion, precipitating fatal acute liver failure in a patient with hepatitis C related chronic liver disease. This case emphasizes the need of inclusion of antibody screening in routine pretransfusion testing as well as a critical role of transfusion medicine specialists for early diagnosis and minimizing transfusion-related morbidity and mortality.