Abstract Aims Advanced heart failure (AHF) is characterized by recurrent episodes of hemodynamic instability, frequent hospitalizations leading to a progressive decline in quality of life, and high mortality rates. The objective of this study was to assess the clinical associations of the MELD score and its efficacy in predicting mortality among patients with AHF. Methods 102 patients with AHF were enrolled, all patients included in the study were on top of tolerated medical therapy according to guidelines. The MELD score was measured at baseline, and every 6 months during follow-up. All patients underwent echocardiographic assessment, six-minute walking test, and cardiopulmonary testing with evaluation of VO2 max and VE/VCO2. Results The mean age of the study group was 57.8±11.9 years. There were 26 deaths during a follow-up period of 31.9±15.4 months. The mean NYHA class was 2.8±0.6, ejection fraction was 26.5±6.3%, TAPSE was 17.5±4.1 mm, and NT-pro-BNP was 2746.0±2475.9 pg/mL. The mean VO2 max was 11.7±3.5 ml/kg/min, and the distance covered in the six-minute walk test was 270.1±151.5 meters. Data stratified by mortality showed that deceased patients had higher NYHA class (2.7±0.6 vs. 3.2±0.3; p<0.001), NT-pro-BNP levels (4767.2±2888.1 vs. 1884.0±1669.5 pg/mL; p<0.001), and MELD score (19.3±3.8 vs. 11.9±5.1; p<0.001) compared to those who were alive at follow-up. Multiple regression analysis revealed a positive correlation between MELD score and NT-pro-BNP (Beta = 0.300; p=0.010), and a negative correlation between MELD score and TAPSE (Beta = -0.236; p=0.026). Cox regression analysis identified MELD score as a predictor of mortality (HR = 1.113; 95%CI = 1.011-1.225; p=0.029), independently by the effect of age, NYHA class, NT-pro-BNP, ejection fraction, TAPSE, and VO2 max. Changes in MELD score percentage, considered as a dichotomous variable (≤100% and >100%), were found to be predictors of mortality. Receiver operating characteristic (ROC) curves showed an area under the curve (AUC) of 0.897 for MELD score and mortality. Conclusions The MELD score and its longitudinal changes are effective predictors of mortality in patients with AHF, regardless of age, NYHA class, and NT-pro-BNP.