We assessed the predictive ability of circulating biomarkers involved in collagen synthesis (procollagen type I N-terminal propeptide [PINP], and procollagen type III N-terminal propeptide [PIIINP], collagen degradation (c-terminal telopeptide of collagen type I [CTx] and mediators of cardiac fibrosis (Galectin-3 and soluble suppression of tumorigenicity 2 protein or sST2) as prognosis markers in 182 subjects with chronic heart failure (HF). In univariate analysis, all markers predicted mortality (except for PINP). A multivariate baseline model was fitted including variables potentially associated with mortality in HF patients. The baseline regression model included age, clinical data and biomarkers. We created four models from the baseline model augmented with the levels of hs-cTnT, CRP and NT-proBNP (model 1), CTx/PIIINP ratio, sST2 and Galectine-3 (model 2), NT-proBNP and sST2 (model 3) and NT-proBNP, CTx/PIIINP ratio and sST2 (model 4), to test whether these biomarkers have an incremental value for predicting mortality. After the addition of all biomarkers to the baseline model, age, CTx/PIIINP ratio and sST2 remained significant predictors. By contrast, Galectin-3 was not significantly associated with mortality. A multimarker strategy, demonstrated that the greatest prognostic improvement was attained with the combined addition of CTx/PIIINP ratio and sST2 highlighting the potential role of fibrosis pathways in risk stratification.