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Background: Although there has been increasing recognition that a substantial part of the cardiovascular, central nervous system, and renal conditions induced by renin-angiotensin-aldosterone system activation reflects an action of aldosterone, the potential influence of therapy designed to block aldosterone has been limited by the fact that spironolactone (until recently the only aldosterone antagonist available) exerts a substantial array of adverse effects. We sought to compare the magnitude of the distress induced by a widely used calcium channel blocking agent, amlodipine, and a new aldosterone antagonist, eplerenone, in patients treated for systolic hypertension., Methods: A total of 269 patients older than 50 years with systolic hypertension were randomized to either eplerenone, 50 mg/d, or amlodipine, 2.5 mg/d, and titrated to a maximum 200-mg eplerenone dose or 10-mg amlodipine dose. Patients were followed up for 24 weeks. Quality-of-life questionnaires (SF-36 Health Survey) and a validated instrument for assessing symptom distress (Symptom Distress Index) were administered at randomization and 24 weeks after starting treatment., Results: The systolic blood pressure response to eplerenone and amlodipine did not differ (eplerenone = -20.5 mm Hg and amlodipine = -20.1 mm Hg). For the quality-of-life analysis, 119 patients were randomized to eplerenone and 122 to amlodipine. No significant treatment group differences in the Symptom Distress Index were detected at baseline. There was an overall significant treatment effect on symptom distress in favor of eplerenone (P =.03). Indeed, Symptom Distress Index showed significant worsening distress in 36 of 71 symptoms in the amlodipine arm and none in the eplerenone arm. Significant treatment effect in favor of eplerenone was observed in 5 symptoms: ankle swelling, weight gain, nocturia, increased urination, and shortness of breath. Patients with symptom distress also showed an erosion of psychosocial measures of quality of life (P<.001)., Conclusions: The aldosterone antagonist eplerenone is substantially better tolerated than the widely used calcium-channel blocking agent amlodipine, with comparable reductions in systolic blood pressure. This feature should improve therapeutics in patients in whom blockade of aldosterone's effect would be helpful.