Fatigue is one of the most common symptoms associated with paroxysmal nocturnal hemoglobinuria (PNH), a rare acquired disorder of hematopoietic stem cells. While it directly impairs lifestyle leading to poor quality of life (QOL), it is not well recognized that fatigue could not depend on the disease activity or percentage of glycosylphosphatidylinositol-deficient granulocyte. We describe the case of a 78-year-old woman, with mild hemolysis and a 20-year history of severe sustained fatigue, whose QOL drastically improved with eculizumab followed by ravulizumab. We also used the novel aplastic anemia and PNH specific QOL tool to evaluate multiple statuses of the patient.