Overwhelming Post-Splenectomy Infection (OPSI or PSS), most frequently caused by encapsulated Gram-positive pathogens, is a complication after splenectomy. Reasons for splenectomy include trauma, or malignant and non-malignant hematologic diseases. OPSI-inducing bacteria are mainly Streptococcus pneumoniae and less frequently Haemophilus influenzae, Neisseria meningitides and Gram-negative bacilli. There exist very efficient--albeit often neglected--strategies, how to prevent infections in patients after splenectomy. These include vaccination, prophylactic antibiotics (always for 3 years during childhood and adolescence) and prompt antibiotic treatment, if an infection is suspected. Patients need to know the nature and likelihood of PSS and they should seek immediate medical attention if they become ill or febrile. Each patient should carry at all times a letter or card documenting the splenectomy. With these measures and precautions, the PSS-risk can be significantly reduced or at best be completely avoided.