Background— Soluble ST2 reflects activity of an interleukin-33–dependent cardioprotective signaling axis and is a diagnostic and prognostic marker in acute heart failure. The use of ST2 in chronic heart failure has not been well defined. Our objective was to determine whether plasma ST2 levels predict adverse outcomes in chronic heart failure in the context of current approaches. Methods and Results— We determined the association between ST2 level and risk of death or transplantation in a multicenter, prospective cohort of 1141 chronic heart failure outpatients. Adjusted Cox models, receiver operating characteristic analyses, and risk reclassification metrics were used to assess the value of ST2 in predicting risk beyond currently used factors. After a median of 2.8 years, 267 patients (23%) died or underwent heart transplantation. Patients in the highest ST2 tertile (ST2 >36.3 ng/mL) had a markedly increased risk of adverse outcomes compared with the lowest tertile (ST2 ≤22.3 ng/mL), with an unadjusted hazard ratio of 3.2 (95% confidence interval [CI], 2.2 to 4.7; P <0.0001) that remained significant after multivariable adjustment (adjusted hazard ratio, 1.9; 95% CI, 1.3 to 2.9; P =0.002). In receiver operating characteristic analyses, the area under the curve for ST2 was 0.75 (95% CI, 0.69 to 0.79), which was similar to N-terminal pro-B–type natriuretic peptide (NT-proBNP) (area under the curve, 0.77; 95% CI, 0.72 to 0.81; P =0.24 versus ST2) but lower than the Seattle Heart Failure Model (area under the curve, 0.81 (95% CI, 0.77 to 0.85; P =0.014 versus ST2). Addition of ST2 and NT-proBNP to the Seattle Heart Failure Model reclassified 14.9% of patients into more appropriate risk categories ( P =0.017). Conclusions— ST2 is a potent marker of risk in chronic heart failure and when used in combination with NT-proBNP offers moderate improvement in assessing prognosis beyond clinical risk scores.