Objectives: This study sought to determine the usefulness of plasma growth differentiation factor 15 (GDF-15) for risk stratification in patients undergoing cardiac surgery in comparison with the additive European System of Cardiac Operative Risk Evaluation (EuroSCORE), N-terminal pro-B-type natriuretic peptide (NTproBNP), and high-sensitive troponin T (hsTNT). Background: GDF-15 is emerging as a humoral marker for risk stratification in cardiovascular disease. No data are available if this marker may also be used for risk stratification in cardiac surgery. Methods: In total, 1,458 consecutive patients were prospectively studied. Pre-operative plasma GDF-15, NTproBNP, hsTNT, clinical outcomes, and 30-day and 1-year mortality were recorded. GDF-15 was determined with a pre-commercial electrochemiluminescence immunoassay. Results: Median additive EuroSCORE (addES) was 5 (interquartile range: 3 to 8); 30-day and 1-year mortality were 3.4% and 7.6%, respectively. Median GDF-15 levels were 1.04 ng/ml (95% confidence interval [CI]: 1.0 to 1.07 ng/ml) in 30-day survivors and 2.62 ng/ml (95% CI: 1.88 to 3.88) in 30-day nonsurvivors (p < 0.0001). C-statistics showed that the area under the curve of a combined model of GDF-15 and addES for 30-day mortality was significantly greater (0.85 vs. 0.81; p = 0.0091) than of the addES alone. For the EuroSCORE categories (0 to 2, 3 to 5, 6 to 10, >10) the presence of GDF-15 ≥1.8 ng/ml resulted in a significant 41.4% (95% CI: 19.2 to 63.7%; p < 0.001) net reclassification improvement and an integrated discrimination improvement of 0.038 (95% CI: 0.022 to 0.0547; p < 0.0001) compared to the model including only the addES, whereas the presence of NTproBNP (cutoff ≥2,000 pg/ml) or hsTNT (cutoff 14 pg/ml) did not result in significant reclassification. Conclusions: The pre-operative plasma GDF-15 level is an independent predictor of post-operative mortality and morbidity in cardiac surgery patients, can further stratify beyond established risk scores and cardiovascular markers, and thus adds important additional information for risk stratification in these patients. (The Usefulness of Growth Differentiation Factor 15 [GDF-15] for Risk Stratification in Cardiac Surgery; NCT01166360).