Objectives. Patients with chronic heart failure (CHF) have an exaggerated immune response, endothelial damage/dysfunction, and increased risk of diabetes mellitus (DM). The inter-relationship(s) between indices of complement activation (soluble membrane attack complex, sMAC), inflammation (hsCRP), endothelial activation (soluble E-selectin, sEsel)), endothelial damage/dysfunction (von Willebrand factor, vWf) and insulin resistance (IR) and prognosis in CHF remains unknown. Design. We investigated the association(s) between plasma sMAC, hsCRP, sEsel, vWf and IR (assessed by homeostatic model assessment, HOMA) in a prospective study including a total of 193 patients with CHF, and assessed whether high levels of these biomarkers had a prognostic impact. Biomarker levels in CHF patients were compared to 100 age-matched controls. Results. Plasma sMAC levels were elevated in patients with CHF due to ischemic heart disease (IHD) as compared with CHF patients with non-ischemic ethiology (p = 0.02), but were not predictive of survival or progression of CHF. A moderate strong relation between sMAC and sEsel levels was found beta = 0.33 (p <0.01), independently of IR and of the presence of DM. In addition, IR was an independent predictor of sMAC in the CHF group beta = 0.37 (p <0.0001). Conclusions. Independent associations between sMAC, sEsel and IR were found in the CHF patients and we hypothesize that IR leading to endothelial activation results in activation of the complement system and thus damaging of the heart tissue