BACKGROUND It is probable that the variety and frequency of delayed adverse vascular events after splenectomy are underappreciated. Splenectomy is performed for a wide variety of conditions, and delayed postsplenectomy hazards are not often studied. OBJECTIVE To estimate the relative risk of adverse vascular events in members of hereditary spherocytosis families who have or have not had a splenectomy. METHODS Members of families in which hereditary spherocytosis exists were systematically questioned about adverse vascular events. RESULTS The cumulative incidence of arterial and venous events at age 70 years was greater in persons who had undergone a splenectomy for spherocytosis (arterial, 22% females, 32% males; venous, 20% females, 19% males) than in affected persons who did not undergo splenectomy (arterial, 3% females, 2% males; venous, 6% females, 4% males) or non-affected family members (arterial, 10% females, 17% males; venous, 4% females, 12% males). Affected subjects who undergo splenectomy are at greatly increased risk of arterial events as compared to affected subjects who do not undergo splenectomy [arterial, hazard ratio (HR) 7.2, 95% confidence interval (CI) 2.8-17.2; venous, HR 3.3, 95% CI 1.1-9.8]. CONCLUSIONS There is a significant, long-lasting, increased risk of adverse arterial and venous thromboembolic events after splenectomy performed for hereditary spherocytosis. A review of the literature indicates that this is also true when splenectomy is performed for several other indications.