Decreased serum levels of high-density lipoprotein (HDL) cholesterol have been shown to be of prognostic significance in patients with severe infectious diseases. Serum HDL cholesterol levels were therefore investigated as a possible parameter for the prediction of clinical outcomes in patients with left-sided infective endocarditis (IE). Fifty-four patients with IE with available admission serum HDL cholesterol levels were included in the study. A clinical outcome was defined as a complicated course during hospitalization. Forty-two patients had complicated courses during their in-hospital stays. The median serum HDL cholesterol level was significantly lower in patients with IE (n = 54) than healthy controls (n = 26) (26 vs 47 mg/dl, p <0.0001). In the 42 patients with complicated courses, the median serum HDL cholesterol level was lower compared with that in 12 patients with uneventful courses (24 vs 36 mg/dl, p = 0.011). A cut point of serum HDL cholesterol level of 25 mg/dl had sensitivity of 62%, specificity of 75%, and a positive predictive value of 90% for predicting clinical outcomes. In conclusion, serum HDL cholesterol levels measured at admission were markedly reduced in patients with left-sided IE. Furthermore, low serum HDL cholesterol levels predicted complicated clinical courses in these patients.