Objectives. We sought to determine whether the beneficial effects of amlodipine in heart failure may be mediated by a reduction in tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels. We postulated that TNF-alpha and IL-6 levels may also have predictive value in patients with congestive heart failure (CHF). Background. The molecular mechanism for progression of CHF may involve cytokine overexpression. The effect of amlodipine on cytokine levels in patients with CHF is unknown. Methods. In the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial, we used enzyme-linked immunosorbent assay to measure plasma levels of TNF-alpha in 92 patients and IL-6 in 62 patients in New York Heart Association functional classes III and IV randomized to receive amlodipine (10 mg/day) or placebo. Blood samples were obtained for cytokine measurement at baseline and at 8 and 26 weeks after enrollment. Results. The baseline amlodipine and placebo groups did not differ in demographics and cytokine levels. Mean (±SD) plasma levels of TNF-alpha were 5.69 ± 0.32 pg/ml, and those of IL-6 were 9.23 ± 1.26 pg/ml at baseline. These levels were elevated 6 and 10 times, respectively, compared with those of normal subjects (p < 0.001). Levels of TNF-alpha did not change significantly over the 26-week period (p = 0.69). However, IL-6 levels were significantly lower at 26 weeks in patients treated with amlodipine versus placebo (p = 0.007 by the Wilcoxon signed-rank test). An adverse event—CHF or death—occurred more commonly in patients with higher IL-6 levels. Conclusions. Amlodipine lowers plasma IL-6 levels in patients with CHF. The beneficial effect of amlodipine in CHF may be due to a reduction of cytokines such as IL-6. (J Am Coll Cardiol 1997;30:35–41)