Leukocyte (WBC) count has been recently identified as an independent predictor of major thrombosis in both essential thrombocythemia (ET) and polycythemia vera (PV). However, whether leukocytosis should be simply considered a marker for vascular disease or whether elevated WBC levels actually contribute directly to causing such disorders is presently matter of many studies. By adopting epidemiologic criteria for causation, we have examined the characteristics to support this association such as (1) strength, (2) consistency, (3) specificity, (4) temporality, (5) biologic gradient, (6) plausibility, (7) experimental evidence, and (8) analogy. Our conclusion supports the notion that baseline leukocytosis in ET and PV patients adds prognostic significance to existing risk factors and that may be considered causative of vascular events. These developments could induce clinicians to incorporate WBC count into standard clinical practice. However, we need prospective clinical studies with stratification of patients according to their baseline leukocyte counts. Until such evidence is available, the decision on how to manage these patients should continue to follow conventional criteria.