Chronic Heart Failure (HF) is a highly prevalent clinical syndrome associated with substantial morbidity and mortality. Apart from cardiac abnormalities leading to decreased cardiac output and/or elevated filling pressures, HF is characterized by multi-organic pathophysiologic implications and neurohumoral adaptions. The concept of biomarkers is attractive and has strikingly improved the disease management of HF with the implementation of natriuretic petides for diagnosis, therapy guidance and risk prediction. However, following the complex and multi-systemic pathophysiology, a single marker is insufficient to cover the global risk in HF and additional markers representing complementary pathways may enhance risk prediction in this vulnerable group of patient. Inflammation plays an important role in the pathogenesis and progression of HF and elevated plasma levels of pro-inflammatory cytokines are associated with an unfavourable outcome. We therefore aimed to investigate, whether circulating immune cells such as CD4+CD28null T cells and humoral markers including soluble urokinase plasminogen activator receptor (suPAR) are relevant prognostic factors in a representative cohort of HF patients. Methods: Patients were enrollend at the outpatient clinic of chronic HF at the Medical University of Vienna. The final study cohort included 319 patients in stable condition. Circulating immune cells were measured with fluorescence-activated cell sorting using fresh EDTA-anticoagulated whole blood. In addition, EDTA plasma samples were centrifuged (2800 rpm, 20min), snap frozen and stored at -80 C for determination of further parameters using enzyme-linked immunosorbent assays (ELISA). Univariate and multivariable Cox proportional hazards models were used to assess the association of determined variables with outcome. Metrics of discrimination and reclassification (Harrells C-statistic, net reclassification improvement and integrated discrimination increment) were used to assess an improvement in risk prediction beyond established risk factors. Results: In the first project, CD4+CD28null T cells were determined in 107 patients and followed for a median time of 23 months. We found that CD4+CD28null T cells were a strong prognosticator of mortality with a hazard ratio per 1-increase of standard deviation (HR per 1-SD) of 1.71 (95% confidence interval [CI]: 1.202.41; P=0.003) in univariate analysis and remained significantly associated with outcome after multivariable adjustment with a HR per 1-SD of 1.88 (95% CI: 1.262.79, P=0.002). In the second project, we investigated the prognostic relevance of suPAR in the total cohort (N=319) and validated the results in a second cohort of patients with chronic HF in advanced stages of the disease (N=343). SuPAR turned out as excellent predictor of outcome with a univariate HR per-1SD of 1.96 (95% CI: 1.63 - 2.35, P<0.001) in univariate analysis and a HR per-1SD of 1.40 (95% CI: 1.06 - 1.86, P=0.019) after ample multivariable adjustment. In a head-to-head comparison suPAR showed a more robust association with outcome than the established prognostic HF biomarker soluble ST2 and further improved metrics of discrimination and reclassification in addition to N-terminal pro B-type natriuretic peptide and the multivariable model, respectively. Of note, results remained largely consistent between the derivation and the validation cohorts. Conclusion: Our results foster the implication of inflammatory processes in the multi-systemic pathophysiology of chronic HF. While the contribution of CD4+CD28null T cells in progression of chronic HF help to further understand underlying pathomechanisms, suPAR may even have future clinical relevance due to the strong association with outcome, marked improvement in risk prediction and ease of determination.