Lysophospholipids (Lyso-PLs) are lipid-derived signaling molecules which were demonstrated to have a strong correlation with the progression of atherosclerosis. In this study, we investigated the influence of high-fat diet on Lyso-PL profiles of atherosclerosis-prone apolipoprotein E-deficient (ApoE(-/-)) mice and wild type C57BL/6 J mice to find out the potential biomarkers associated with atherosclerosis. Firstly, the quantitative profiling method for Lyso-PLs based on ultra-performance liquid chromatography quadrupole linear ion trap mass spectrometry (UPLC-QTRAP-MS/MS) was established and validated. Secondly, this method was utilized to quantify 169 targeted Lyso-PLs in plasma samples of ApoE(-/-) mice and wild type C57BL/6 J mice collected at different time points. Finally, 12 of 37 differential LysoPLs were identified as more reliable biomarkers by integrating static metabolomics and time-dependent analyses, among which Lyso-PC/15:0, 18:1/Lyso-PI, 22:5/Lyso-PI and 22:4/Lyso-PI were highly correlated with TCand LDL-C levels. Meanwhile, we found that the Lyso-PL profiles of ApoE(-/-) mice and C57BL/6 J mice were distinguished by altered metabolism of different Lyso-PLs classes, while C57BL/6 J mice fed with high-fat diet and normal diet were discriminated by the content differences of Lyso-PLs with same fatty acid composition. In conclusion, these results provided detailed changes of Lyso-PL profiles associated with atherosclerosis and the differential Lyso-PLs with reasonable change trends may serve as promising biomarkers for atherosclerosis progression. (C) 2019 Elsevier B.V. All rights reserved.