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]. CONCLUSION: 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.