(1) Background: The optimal treatment of septic cardiomyopathy (SCM) remains questionable. The aim of the study was to compare the treatment of SCM based on levosimendan versus the best available therapy. (2) Methods: We conducted an observational study including patients with severe septic cardiomyopathy and circulatory failure. (3) Results: Fourteen patients (61%) received levosimendan, and nine received other treatments. The patients in the levosimendan group were more severely ill [APACHE II: 23.5 (14, 37) vs. 14 (13, 28), respectively,p= 0.012], and there was a trend for more decompensated LV function depicted by the LVEF [15% (10, 20) vs. 25% (5, 30), respectively,p= 0.061]. However, they presented a significantly higher increase in LVEF after seven days [15% (10, 20) to 50% (30, 68) (p< 0.0001) vs. 25% (5, 30) to 25% (15, 50) (p= 0.309), and a significantly higher decrease in lactate levels during the first 24 h [4.5 (2.5, 14.4) to 2.85 (1.2, 15),p= 0.036 vs. 2.9 (2, 18.9) to 2.8 (1, 15),p= 0.536]. Seven-day survival (64.3% vs. 33.3%,p= 0.424) and ICU survival (50% vs. 22.2%,p= 0.172) were higher in the first group, although differences did not reach statistical significance. The degree of left ventricular impairment and the magnitude of EF improvement by the seventh-day post-SCM onset were associated with mortality in regression analysis. (4) Conclusions: Our study presents main hemodynamic data supporting the possible efficacy of levosimendan treatment in patients with severe SCM.