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α-Defensins are part of the innate immune system. Low-grade inflammation seems to play a crucial role in development and progression of chronic heart failure (CHF). The aims of the present study were to compare plasma levels of α-defensins in CHF patients and healthy controls and to examine the predictive ability of α-defensins, alone and combined with N-terminal pro brain natriuretic peptide (NT-proBNP), with respect to all-cause mortality.In a prospective observational study lasting 2.6 years we examined the prognostic value of plasma α-defensins with respect to mortality in 194 CHF patients, and compared plasma levels with those of 98 age-matched healthy controls. α-Defensin levels were twice as high among CHF patients in New York Heart Association (NYHA) functional class III–IV than in patients in NYHA class I–II and healthy controls (P = 0.001). The absolute increase in risk of mortality for patients with α-defensin levels in the upper tertile vs. the lowest tertile was 30% (P = 0.002). After adjusting for potential confounders including NT-proBNP, plasma α-defensins remained independently associated with an increased risk of all-cause mortality (hazard ratio 1.65, 95% confidence interval 1.19–2.28, P = 0.002) per 1 standard deviation increment in Ln (natural logarithm)-transformed α-defensin values. The combination of high α-defensins and NT-proBNP levels provided incremental prognostic information independent of well-known prognostic biomarkers in heart failure.Plasma α-defensins appear to have prognostic information regarding mortality among patients with CHF and seem to provide incremental information to established clinical risk markers.