Systolic hypertension is very common in the elderly and is strongly associated with the risk of cardiovascular and cerebrovascular events. The control of systolic hypertension is difficult and most patients require combination antihypertensive therapy. Few data are available regarding the efficacy of angiotensin II receptor antagonists on systolic hypertension of the elderly. The aim of this double-blind, double-dummy, randomized, parallel-group, multicenter study was to assess the efficacy of eprosartan 600 mg in combination with hydrochlorothiazide (HCTZ) 12.5 mg in comparison with losartan 50 mg in combination with HCTZ 12.5 mg, in reducing blood pressure in elderly patients with grade 2 systolic hypertension who did not optimally respond to eprosartan or losartan monotherapy. After a 3-week placebo wash-out, 155 patients with an Office trough sitting systolic blood pressure (Office sitSBP) >or=160 mmHg and <180 mmHg were randomized to eprosartan 600 mg (n=78) or losartan 50 mg (n=77) once daily for 6 weeks. In patients not optimally responding to monotherapy (Office sitSBP>or=130 mmHg) 12.5 mg HCTZ was added as fixed combination once daily for 6 weeks. A 24-hour ambulatory blood pressure monitoring (ABPM) was performed at the end of wash-out and at the end of the fixed-combination period. No statistically significant difference was found between eprosartan/HCTZ and losartan/HCTZ on the primary endpoint (24-hour ABPM SBP) with an adjusted mean difference between treatments of 3.1 mmHg (95% CI: -0.32-6.59). However, the mean 24-hour ABPM SBP significantly decreased by 16.7 mmHg with eprosartan/HCTZ and 20.3 mmHg with losartan/HCTZ (P<0.001 vs. baseline). The mean Office sitSBP significantly decreased by 28.7 mmHg and 29.6 mmHg respectively, with eprosartan/HCTZ and losartan/HCTZ (P<0.001 vs.baseline and vs. monotherapy). In this study, eprosartan/HCTZ did not demonstrate to be superior to losartan/HCTZ in reducing ABPM systolic hypertension in the elderly.