Immune dysfunction has been postulated to play a role in the pathophysiology of chronic heart failure. We examined the relation between interleukin-6 (IL-6) production and natural killer (NK) cell dysfunction in patients with chronic heart failure. Sera and peripheral blood mononuclear cells (PBMCs) were collected from 82 patients with advanced heart failure. Levels of circulating NK cells and T cells were determined by flow cytometry. NK cell function was measured by standard cytotoxicity assays. IL-6 in supernatants of PBMC cultured in vitro was quantitated by an enzyme-linked immunosorbent assay. The levels of circulating NK cells were lower in patients with heart failure than in normal controls (p = 0.0037). NK cells from patients with heart failure also exhibited impaired cytolytic functions in the absence of stimuli and in response to IL-2 and IL-12 (p <0.0001 for all conditions). PBMCs from patients with heart failure produced higher levels of IL-6 in response to a T-cell stimulus than did PBMCs from healthy controls (p = 0.0012). The level of IL-6 produced by unstimulated PBMCs in patients with heart failure correlated with NK cell cytolytic impairment (p = 0.0012). These results demonstrated that PBMCs are a source of IL-6 in patients with heart failure. Production of IL-6 by PBMCs correlated with NK cell anergy to other cytokines that use signal transduction pathways that may be regulated by IL-6. These results support a model of cytokine-induced anergy in conditions that result in high systemic levels of IL-6.