Patients who lack a functioning spleen become vulnerable to sepsis caused by bacteria and, occasionally, protozoa. The risk is higher in children and in those who have had immunosuppressive treatment, and the risk remains lifelong. Overwhelming post-splenectomy infection (OPSI) occurs at an estimated incidence of 0.23-0.42% per year, with a lifetime risk of 5%. Episodes of OPSI are emergencies, requiring immediate parental antibiotics and intensive care; intravenous immunoglobulins may be useful. OPSI carries a mortality of 38-69%. Streptococcus pneumoniae is the commonest infecting organism, accounting for 50-90% of isolates from blood cultures in reported series; it is particularly common in children with sickle cell disease. Less commonly, the infecting organisms are other bacteria, Babesia or Ehrlichia. OPSI may be, to some extent, preventable by several interventions. These are surgical conservation of the spleen; immunization against S. pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis; prophylactic antibiotics; stand-by antibiotics; patient information sheets; and a medical alert bracelet. Asplenic patients living in malaria-endemic areas require optimal prophylaxis. The initial step in prevention of OPSI is the creation of an asplenia register, as many patients are not covered by these simple measures.