Background: Follistatin-like 1 (FSTL1) is an extracellular glycoprotein found in human serum. Recent work suggests that FSTL1 is secreted in response to ischemic injuries and that its overexpression is protective in the heart and vasculature. Methods and Results: We examined serum FSTL1 levels in patients with chronic heart failure with left ventricular (LV) ejection fraction <40% (n = 86). The sample was separated into three tertiles of patients with low, medium, and high FSTL1 levels. Serum FSTL1 was increased 56% above age-and sex-matched healthy controls. Diabetes mellitus, brain natriuretic peptide level, left atrial size, LV posterior wall thickness, LV end-diastolic diameter, and LV mass were significant determinants of FSTL1 serum levels by bivariate analysis. After controlling for significant covariates, FSTL1 levels predicted LV hypertrophy (as measured by LV mass index) by multivariate linear regression analysis (P<0.001). Unadjusted survival analysis demonstrated increased mortality in patients with increasing FSTL1 levels (P=0.09). After adjusting for significant parameters, patients with increased FSTL1 remained at the highest risk of death (hazard ratio, 1.028; 95% CI, 0.98 to 1.78; P=0.26). To determine whether elevated FSTL1 levels may be derived from the myocardium, FSTL1 protein expression was measured in explanted failing (n = 18) and nonfailing (n=7) human hearts. LV failing hearts showed 2.5-fold higher FSTL1 protein levels over nonfailing control hearts (P<0.05). Conclusions: Elevated serum FSTL1 in patients with heart failure was associated with LV hypertrophy. Further studies on the role of FSTL1 as abiomarker in chronic systolic heart failure are warranted.