OBJECTIVE: To assess the prognostic value of the pro-apoptotic, but also cell growth-inducing molecule soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) in heart failure (HF). METHODS: We assayed sTWEAK levels in 351 patients with advanced HF (non-ischemic: 130, ischemic: 221). During a median follow-up of 4.9 years, 195 patients (56%) died. RESULTS: sTWEAK concentrations were associated with extended survival in patients with non-ischemic (P=0.022), but not with ischemic HF (P=0.82). The inverse association in non-ischemic HF remained significant in a multivariable Cox regression model (P=0.025) with a hazard ratio of 0.40 (95% confidence interval: 0.21-0.77) comparing the third to the first tertile (P=0.007). CONCLUSION: Low sTWEAK levels independently predict mortality in advanced non-ischemic HF. sTWEAK-induced proliferation of cardiomyocytes may explain its impact on suvival. The different prognostic value of sTWEAK in ischemic and non-ischemic HF may point towards distinct pathogenic pathways determining the course of disease.