Levels of high-density lipoprotein cholesterol (HDL-C) are inversely associated with the incidence of coronary artery disease (CAD). However, the underlying mechanism of CAD in the context of elevated HDL-C levels is unclear. Our study aimed to explore the lipid signatures in patients with CAD and elevated HDL-C levels and to identify potential diagnostic biomarkers for these conditions. We measured the plasma lipidomes of forty participants with elevated HDL-C levels (men with >50 mg/dL and women with >60 mg/dL), with or without CAD, using liquid chromatography–tandem mass spectrometry. We analyzed four hundred fifty-eight lipid species and identified an altered lipidomic profile in subjects with CAD and high HDL-C levels. In addition, we identified eighteen distinct lipid species, including eight sphingolipids and ten glycerophospholipids; all of these, except sphingosine-1-phosphate (d20:1), were higher in the CAD group. Pathways for sphingolipid and glycerophospholipid metabolism were the most significantly altered. Moreover, our data led to a diagnostic model with an area under the curve of 0.935, in which monosialo-dihexosyl ganglioside (GM3) (d18:1/22:0), GM3 (d18:0/22:0), and phosphatidylserine (38:4) were combined. We found that a characteristic lipidome signature is associated with CAD in individuals with elevated HDL-C levels. Additionally, the disorders of sphingolipid as well as glycerophospholipid metabolism may underlie CAD.