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Aims This study investigates the role of osteoprotegerin (OPG) and growth‐differentiation factor 15 (GDF‐15) as predictors of outcome in cardiogenic shock (CS) complicating acute myocardial infarction. The novel biomarkers OPG and GDF‐15 have shown prognostic impact in various cardiovascular diseases including myocardial infarction. In acute myocardial infarction complicated by CS, the diagnostic and prognostic impact of these biomarkers has not been investigated yet. OPG and GDF‐15 may have additional prognostic impact on early prognosis assessment, being potentially useful for decision‐making in CS. Methods and results In the randomized Intra‐aortic Balloon Pump in cardiogenic Shock II (IABP‐SHOCK II)‐trial, 600 patients with CS complicating acute myocardial infarction undergoing early revascularization were assigned to therapy with or without IABP. Within a pre‐defined substudy, blood samples were collected from 190 patients during PCI. GDF‐15 and OPG serum levels were measured with standard enzyme‐linked immunosorbent assay kits. Patients with GDF‐15 and OPG levels greater than the median showed higher rates of death at 30 days by χ2 testing (OPG, 51% vs. 32%, P = 0.01; GDF‐15, 52% vs. 31%, P = 0.005) and log rank testing [GDF‐15, hazard ratio (HR) 1.88, 95% confidence interval (CI) 1.21–2.94; P = 0.005; OPG, HR 1.74, 95% CI 1.11–2.71; P = 0.01]. Both markers were significantly predictive of 30‐day mortality in univariable logistic regression analysis. In a multivariable logistic stepwise regression model, GDF‐15, TIMI (Thrombolysis In Myocardial Infarction) flow grade <3 after PCI, age, LVEF, and serum lactate remained significant predictors of 30‐day mortality. Conclusion GDF‐15 on admission is a significant independent predictor of short‐term mortality in infarct‐related CS. Trail registration: NCT00491036

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