Background - Although present guidelines suggest that treatment of hypertension is more effective in patients with multiple risk factors and higher risk of cardiovascular events, this hypothesis was never verified in older patients with systolic hypertension. Methods and Results - Using data from the Systolic Hypertension in the Elderly Program, we calculated the global cardiovascular risk score according to the American Heart Association Multiple Risk Factor Assessment Equation in 4,189 participants free of cardiovascular disease (CVD) and in 264 participants with CVD at baseline. In the placebo group, rates of cardiovascular events over 4.5 years were progressively higher according to higher quartiles of CVD risk. The protection conferred by treatment was similar across quartiles of risk. However, the numbers needed to treat (NNTs) to prevent one cardiovascular event were progressively smaller according to higher cardiovascular risk quartiles. In participants with baseline CVD, the NNTs to prevent one cardiovascular event were similar to those estimated for CVD-free participants in the highest-risk quartile. Conclusions - Treatment of systolic hypertension is most effective in older patients who, because of additional risk factors or prevalent CVD, are at higher risk of developing a cardiovascular event. These patients are prime candidates for antihypertensive treatment.