Introduction: Myocardial infarction with ST-segment elevation (STEMI) is the coronary artery disease associated with the highest risk of morbimortality; however, this risk is heterogeneous, usually being evaluated by clinical scores. Risk assessment is a key factor in personalized clinical management of patients with this disease. Aim: The aim of this study was to assess whether some new cardiac biomarkers considered alone, combined in a multibiomarker model or in association with clinical variables, improve the short- and long-term risk stratification of STEMI patients. Materials and Methods: This was a retrospective observational study of 253 patients with STEMI. Blood samples were obtained before or during the angiography. The assessed biomarkers were C-terminal fragment of insulin-like growth factor binding protein-4 (CT-IGFBP4), high sensitive cardiac troponin T (hs-cTnT), N-terminal fragment of probrain natriuretic peptide (NT-proBNP), and growth differentiation factor 15 (GDF-15); they reflect different cardiovascular (CV) physiopathological pathways and underlying pathologies. We registered in-hospital and follow-up mortalities and their causes (cardiovascular and all-cause) and major adverse cardiac events (MACE) during a two year follow-up. Discrimination, survival analysis, model calibration, and reclassification of the biomarkers were comprehensively evaluated. Results and Discussion: In total, 55 patients (21.7%) died, 33 in-hospital and 22 during the follow-up, most of them (69.1%) from CV causes; 37 MACE occurred during follow-up. Biomarkers showed good prognostic ability to predict mortality, alone and combined with the multibiomarker model. A predictive clinical model based on age, Killip–Kimball class, estimated glomerular filtration rate (eGFR), and heart rate was derived by multivariate analysis. GDF-15 and NT-proBNP significantly improved risk assessment of the clinical model, as shown by discrimination, calibration, and reclassification of all the end-points except for all-cause mortality. The combination of NT-proBNP and hs-cTnT improved CV mortality prediction. Conclusions: GDF-15 and NT-proBNP added value to the usual risk assessment of STEMI patients.