BACKGROUND: ST2 is involved in cardioprotective signaling in the myocardium and has been identified as a potentially promising biomarker in heart failure (HF). We evaluated ST2 levels and their association with functional capacity and long-term clinical outcomes in a cohort of ambulatory patients with HF enrolled in the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) study-a multicenter, randomized study of exercise training in HF. METHODS AND RESULTS: HF-ACTION randomized 2331 patients with left ventricular ejection fraction <0.35 and New York Heart Association class II to IV HF to either exercise training or usual care. ST2 was analyzed in a subset of 910 patients with evaluable plasma samples. Correlations and Cox models were used to assess the relationship among ST2, functional capacity, and long-term outcomes. The median baseline ST2 level was 23.7 ng/mL (interquartile range, 18.6-31.8). ST2 was modestly associated with measures of functional capacity. In univariable analysis, ST2 was significantly associated with death or hospitalization (hazard ratio, 1.48; P<0.0001), cardiovascular death or HF hospitalization (hazard ratio, 2.14; P<0.0001), and all-cause mortality (hazard ratio, 2.33; P<0.0001; all hazard ratios for log2 ng/mL). In multivariable models, ST2 remained independently associated with outcomes after adjustment for clinical variables and amino-terminal pro-B-type natriuretic peptide. However, ST2 did not add significantly to reclassification of risk as assessed by changes in the C statistic, net reclassification improvement, and integrated discrimination improvement. CONCLUSIONS: ST2 was modestly associated with functional capacity and was significantly associated with outcomes in a well-treated cohort of ambulatory patients with HF although it did not significantly affect reclassification of risk. CLINICAL TRIAL INFORMATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00047437.