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Background—Soluble ST2 (sST2), a biomarker related to inflammation, is associated with outcomes of patients with heart failure (HF). In depth analyses of the relationship between sST2, changes in sST2 and patient outcomes are reported. Methods and Results—sST2 was measured at baseline (n=1,650), 4-months (n=1,345) and 12-months (n=1,094) in Valsartan Heart Failure Trial. Baseline sST2 averaged 28.7±16.2 ng/mL; significantly (p<0.001) higher in men than women, but supra-normal in only 9 and 15%, respectively. A continuous relationship between sST2 and the log hazard ratio for outcomes was modeled as two linear segments with a significant decrease in the rate of increase in hazard ratios above 33.2 ng/mL. Each segment of the sST2 distribution was significantly (p<0.0001) associated with the risks of morbid event, mortality and hospitalization for HF. Only sST2 values <33.2 ng/mL were significantly related to the outcomes when 23 readily available clinical variables including NT-proBNP were included in the Cox regression model. sST2 didn’t improve discrimination of patient outcomes. Compared to placebo, valsartan significantly (p<0.001) reduced the rate of increase in sST2. Increases in sST2 over 12-months, but not decreases, were significantly associated with subsequent outcomes independent of clinica