Stroke is a critical complication of Sickle Cell Disease (SCD) and is predicted by increased transcranial Doppler velocities. Recent computational fluid dynamic studies demonstrate a combination of high flow and vessel tortuosity are responsible for high TCD velocities. We determined the predictors of vessel tortuosity in control subjects and SCD patients without known vasculopathy. We applied three different tortuosity metrics (distance measure, inflection count, and sum of angles method) to middle cerebral artery segments measured in 19 SCD patients and 13 controls. Both distance and inflection count metrics were increased in SCD patients but the distance metric was more discriminatory. Age and hemoglobin levels were the strongest predictors of tortuosity in SCD patients. Both terms were retained in multivariate analysis, suggesting that chronic anemia exacerbates the normal increase in vessel tortuosity with age.