ST-elevation myocardial infarction (STEMI) is one of the main reasons for morbidity and mortality worldwide. In addition to the classic biomarker NT-proBNP, new biomarkers like ST2 and Pentraxin-3 (Ptx-3) have emerged as potential tools in stratifying risk in cardiac patients. Indeed, multimarker approaches to estimate prognosis of STEMI patients have been proposed and their potential clinical impact requires investigation. In our study, in 147 patients with STEMI, NT-proBNP as well as serum levels of ST2 and Ptx-3 were evaluated. During two-year follow-up (FU; 734.2 ± 61.2 d) results were correlated with risk for cardiovascular mortality (CV-mortality). NT-proBNP (HR = 1.64, 95% CI = 1.21–2.21, p = 0.001) but also ST2 (HR = 1.000022, 95% CI = 1.00–1.001, p < 0.001) were shown to be reliable predictors of CV-mortality, while the highest predictive power was observed with Ptx-3 (HR = 3.1, 95% CI = 1.63–5.39, p < 0.001). When two biomarkers were combined in a multivariate Cox regression model, relevant improvement of risk assessment was only observed with NT-proBNP+Ptx-3 (AIC = 209, BIC = 214, p = 0.001, MER = 0.75, MEV = 0.64). However, the highest accuracy was seen using a three-marker approach (NT-proBNP + ST2 + Ptx-3: AIC = 208, BIC = 214, p < 0.001, MER = 0.77, MEV = 0.66). In conclusion, after STEMI, ST2 and Ptx-3 in addition to NT-proBNP were associated with the incidence of CV-mortality, with multimarker approaches enhancing the accuracy of prediction of CV-mortality.