Background Growth differentiation factor (GDF)-15 has been shown to predict cardiovascular (CV) outcomes in acute coronary syndrome (ACS) using non-commercial assays. We evaluated the prognostic performance of GDF-15 measured with the first clinically available assay. Furthermore, we evaluated whether GDF-15 was associated with CV death or heart failure (HF) across the spectrum of risk in non-ST-segment elevation (NSTE)-ACS. Methods We measured baseline GDF-15 (Roche, Elecsys) in 4330 patients with NSTE-ACS enrolled in MERLIN-TIMI 36. Patients were categorized using a priori thresholds of GDF-15 levels (<1200, 1200–1800, ≥1800 ng/L) and stratified according to estimated clinical risk per TIMI risk score (0–2, 3–4, and ≥5). Cox modeling included age, sex, BMI, smoking, HF, diabetes, renal function, NT-proBNP, hsTnT, and hsCRP. Results There were 2286 (53%), 1104 (25%), and 940 (22%) pts with GDF-15 <1200, 1200–1800, and ≥1800 respectively. GDF-15 was significantly associated after multivariable adjustment with CV death/HF modeled either as a categorical (1200–1800 ng/L: Adj hazard ratios [HR] 1.55 [1.09–2.19]; ≥1800 ng/L: Adj HR 1.94 [1.34–2.79]) or continuous variable (Adj HR 1.36 [1.16–1.60] per 1-unit increase in log 2 -transformed GDF-15). Notably, there was an interaction (P interaction =0.003) between TIMI risk score and GDF-15, with GDF-15 identifying the greatest incremental relative risk in those at lowest risk based on the TIMI risk score alone. Conclusions Using a clinically available assay, GDF-15 can be applied using established cut-off points to independently predict risk of CV death/HF in patients with NSTE-ACS. This incremental risk appears to be particularly robust among individuals traditionally identified as low risk.