Heart failure is characterized by activation of the immune system which is strongly associated with disease severity and outcome. We sought to compare the prognostic impact of two established inflammatory markers — interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) — in patients with chronic heart failure. In stable, optimally managed outpatients with chronic heart failure, baseline levels of hsCRP and IL-6 were determined. Clinical follow-up was obtained and the rate of events (heart failure related deaths or hospitalizations) were recorded. We included 201 patients (32.7% female, NYHA class II [66.2%] or III [33.8%], mean age 70 years). During a median follow up of 614 (367−761) days, 64 (30.9%) patients experienced an event; those with an event had higher levels of hsCRP (median 2.93 [interquartile range 2.36−8.92] vs 2.23 [1.32−5.77] mmol/l) and IL-6 (7.8 [4.7−10.3] vs 4.3 [2.6−7.9] pg/ml). However, on Cox multivariate analysis, IL-6 but not hsCRP emerged as an independent predictor of prognosis (hazard ratio HRadjusted 2.74, 95% confidence interval 1.17−6.43; P = 0.020). Our findings suggest that IL-6 is a better prognostic predictor than hsCRP in patients with chronic stable heart failure.