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Heart transplantation (HT) is the gold standard therapy for advanced heart failure (ADHF), and LVADs as destination therapy are an option in non-HT candidates. Most patients with ADHF never receive HT or an LVAD, so alternative strategies are needed. Intermittent levosimendan can reduce HF hospitalizations in ADHF patients in the short term. It is uncertain whether the results of the comparison of inotropes with older-generation LVADs would have the same outcomes in the current era of ADHF patients treated with levosimendan, who are less sick but older. In this paper, we compare the use of two therapeutic strategies for end-stage HF in patients who are not candidates for HT: repetitive intermittent levosimendan vs. LVAD as destination therapy. To do so, we compare two multicenter cohorts of real-life patients from Spain: the LEVO-D registry and the REGALAD registry. In total, 715 patients coming from the two registries were found: 403 from LEVO-D and 312 from REGALAD. Non-adjusted median survival was shorter for LEVO-D patients, with the benefit for the LVADs seen only after the first year of therapy. The survival advantage for the LVAD cohort was also true after analysis of the matched cohort but, as in the non-matched analysis, the survival benefit was mainly shown after one year of follow-up. We conclude that in elderly ADHF non-HT candidates, LVAD therapy offers significantly better long-term outcomes when compared to intermittent levosimendan; thus, it should be considered in carefully selected candidates. On the other hand, in poor LVAD candidates or highly comorbid patients, intermittent inotropic support with levosimendan could be a reasonable alternative to LVAD, as 1-year outcomes are similar.