New parameters and markers are constantly being sought to help better assess patients with heart failure (HF). ST2 protein has gained interest as a potential biomarker in cardiovascular disease. It is known that the IL-33/ST2L system belongs to the cardioprotective pathway, which prevents the fibrosis, hypertrophy, and apoptosis of cardiomyocytes and also inhibits the inflammatory response. Soluble ST2 (sST2) is involved in the immune response and secreted in response to the mechanical overload of the myocardium, thus providing information on the processes of myocardial remodeling and fibrosis. A total of 110 hospitalized patients diagnosed with heart failure with reduced ejection fraction (HFrEF) were included in the study. Clinical and biochemical parameters were studied. During the follow-up, 30.9% patients died and 57.3% patients reached the composite endpoint. Using ROC curves, the reference cut-off point for sST2 was determined to be 45.818 pg/mL for all-cause deaths. Significantly higher concentrations of inflammatory parameters and natriuretic peptides were found in the group of patients with higher sST2 concentrations. sST2 protein is an independent risk factor for all-cause deaths of patients with HFrEF.