Very late sepsis in splenectomized patients with hereditary spherocytosis has been seen rarely up to now; the frequency and the immunodeficiency causing it are largely unknown. Within the past 7 years we have learned of four cases of sepsis or meningitis (three fatal) in adult patients with hereditary spherocytosis who had been splenectomized years earlier. The estimated frequency of very late postsplenectomy infections is 0.69 cases of sepsis or meningitis in 1000 patient-years (0.46 deaths in 1000 patient-years). Pneumococci were proven in two patients. The surviving patient showed low antibody titers against pneumococcal serotypes even after pneumococcal meningitis and subsequent vaccination. There have been several reports of an insufficient response to pneumococcal vaccination in patients with severe infections. We recommend determination of pneumococcal antibody titers after immunization in every splenectomized patient: Nonresponders to vaccination may be at high risk for overwhelming postsplenectomy infection. Our data demonstrate that there is a lifelong risk for severe postsplenectomy infections and therefore the lasting need for immediate antibiotic therapy in any case with sudden onset of high fever.