The association between leukocytosis and increased morbidity and mortality of ischemic vascular disease has been observed for more than half a century, and recent studies in >350 000 patients confirm the robustness of the association and the dramatically higher relative and absolute acute and chronic mortality rates in patients with high versus low leukocyte counts. Although there is reason to believe that the association is not causal (that is, that leukocytosis is simply a marker of inflammation), there is also reason to believe that the leukocytosis directly enhances acute thrombosis and chronic atherosclerosis. Leukocytosis also is associated with poor prognosis and vaso-occlusive events in patients with sickle cell disease, and experimental data suggest a direct role for leukocytes in microvascular obstruction. The only way to test whether leukocytes contribute directly to poor outcome in ischemic cardiovascular disease is to assess the effect of modifying leukocyte function or number. Because selective blockade of leukocyte integrin αMβ2 and P-selectin have thus far been disappointing as therapeutic strategies in human cardiovascular and cerebrovascular disease, I discuss the potential risks and benefits of short-term treatment with hydroxyurea to decrease the leukocyte count in select populations of patients at the highest risk of short-term death.