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(1) Background: Simple parameters to be used as early predictors of prognosis in infective endocarditis (IE) are lacking. The aim of this study was to evaluate the prognostic role of high-density-lipoprotein cholesterol (HDL-C) and also of total-cholesterol (TC), low-density-lipoprotein cholesterol (LDL-C), and triglycerides, in relation to clinical features and mortality, in IE. (2) Methods: Retrospective analysis of observational data from 127 consecutive patients with a definite diagnosis of IE between 2016 and 2019. Clinical, laboratory and echocardiography data, mortality, and co-morbidities were analyzed in relation to HDL-C and lipid profile. (3) Results: Lower HDL-C levels (p = 0.035) were independently associated with in-hospital mortality. HDL-C levels were also significantly lower in IE patients with embolic events (p = 0.036). Based on ROC curve analysis, a cut-off value was identified for HDL-C equal to 24.5 mg/dL for in-hospital mortality. HDL-C values below this cut-off were associated with higher triglyceride counts (p = 0.008), higher prevalence of S. aureus etiology (p = 0.046) and a higher in-hospital mortality rate (p = 0.004). Kaplan–Meier survival analysis showed higher 90-day mortality in patients with HDL-C ≤ 24.5 mg/dL (p = 0.001). (4) Conclusions: Low HDL-C levels could be used as an easy and low-cost marker of severity in IE, particularly to predict complications, in-hospital and 90-day mortality.

Prognostic Value of Decreased High-Density Lipoprotein Cholesterol Levels in Infective Endocarditis