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Introduction Advanced heart failure (AHF) is characterized by repeated episodes of hemodynamic instability, frequent hospitalizations with progressive reduction in quality of life. The aim of the study was to verify in a small group of patients, no longer susceptible to heart transplantation (HT) and left ventricular assistance (LVAD), the effectiveness of monthly treatment with Levosimendan for a period of at least 6 months on quality of life and hospitalization. Materials and methods 29 elderly patients (≥65 years) with AHF, excluded from the waiting list for HT or no longer eligible for inclusion on the waiting list were enrolled. 12 patients practiced at least 1 infusion of Levosimendan and were considered as cases, while 17 patients with maximized treatment were used as controls. All patients underwent a multidimensional evaluation in which Fraity was assessed according to Fried criteria, cognitive function with Mini-Mental State Examination (MMSE), depressive symptoms with Geriatric Depression Scale (GDS). Results The 29 patients were followed up monthly and the 12 patients of Levosimendan group practiced an average of 4.6±2.7 infusions in absence of adverse events. The mean age was 73.3±6.2, 87.5% males, with a NYHA class of 3.4±0.4, an ejection fraction of 26.6±4.9 and NT-pro-BNP value of 7016.8±4876.1. Renal function was impaired with eGFR (ml / min) = 36.8±20.1. These patients had been hospitalized 1.8±0.7 times in the previous year. The data are not statistically different compared to the control group although a greater severity of the clinical condition of the case group is evident. The 6 minute walking test (6MWT) was 201.4±118.1 meters. The mean values of Frailty was 4.6±0.5, the GDS 6.4±4.2 and the MMSE 23.8±4.3. Only the MMSE was lower in the case group than in the controls (26.9±1.9, p=0.022). The results in terms of pre-post treatment difference identify an improvement of 35.3±136.3 meters at 6MWT in patients treated with Levosimendan compared to −72.2±94.2 meters in controls (p=0.030), Frailty is reduced by 1.4±1.6 points compared to 0.1±1.1 in controls (p=0.030), the GDS decreases by 0.9±1.5 in cases and increases by 2±2.1 in the control group (p=0.020), the MMSE score increases by 2.12±4.1 in treated patients, while it is reduced by 2.75±2.3 in the control group; p=0.003. The eGFR is reduced in both groups although more in the controls (−1.87±5.8 vs −10.8±11.1; p=0.043). There are no significant differences in mortality while there was less hospitalization during the follow-up period 0.9±0.6 vs 2.4±1.5; p=0.016). Multiple regression analysis shows that hospitalizations reduction is correlated with the recovery of frailty. This association is independent by age and disease severity. Conclusion Levosimendan improves physical and cognitive function, at the same time a minor decrease in renal function is observed, with a reduction of unscheduled visits to the hospital. Funding Acknowledgement Type of funding sources: None.