The Systolic Hypertension in Europe (Syst-Eur) study investigated whether antihypertensive treatment could decrease the risk of cardiovascular complications in elderly patients with isolated systolic hypertension. Patients > or = 60 years were randomly assigned to treatment with the dihydropyridine calcium antagonist nitrendipine (n = 2,398), with the addition of enalapril and hydrochlorothiazide if needed, or to matching placebo (n = 2,297). In the intent-to-treat analysis, the between-group difference in blood pressure was 10.1/4.5 mm Hg (p < 0.001). Active treatment decreased the total incidence of stroke (the primary endpoint) by 42% (p = 0.003), of all cardiac endpoints by 26% (p = 0.03), and of all cardiovascular endpoints combined by 31% (p < 0.001). Cardiovascular mortality was somewhat lower with active treatment (-27%, p = 0.07); all-cause mortality was not significantly different (-14%; p = 0.22). For total (p = 0.009) and cardiovascular (p = 0.09) mortality, the benefit of antihypertensive treatment weakened with advancing age and for total mortality it decreased with lower systolic blood pressure at entry (p = 0.05). The benefits of active treatment were not independently related to gender or to the presence of cardiovascular complications at entry. Antihypertensive therapy was at least as effective in patients with diabetes as in those without diabetes at entry. Further analyses suggested benefit in patients who were taking nitrendipine as monotherapy. Per-protocol analysis largely confirmed the intent-to-treat results. Active treatment decreased all strokes by 44% (p = 0.004), all cardiac endpoints by 26% (p = 0.05), and all cardiovascular endpoints by 32% (p < 0.001). Total mortality was decreased by 26% (p = 0.05), but the similar reduction in cardiovascular mortality did not reach significance in this analysis. It is concluded that stepwise antihypertensive drug treatment starting with nitrendipine improves prognosis in elderly patients with isolated systolic hypertension.