ABSTRACT: Aortic dissection (AD) is a catastrophic cardiovascular emergency with a poor prognosis, and little preceding symptoms. Abnormal lipid metabolism is closely related to the pathogenesis of AD. However, comprehensive lipid alterations related to AD pathogenesis remain unclear. Moreover, there is an urgent need for new or better biomarkers for improved risk assessment and surveillance of AD. Therefore, an untargeted lipidomic approach based on ultra-high-performance liquid chromatograph-mass spectrometry was employed to unveil plasma lipidomic alterations and potential biomarkers for AD patients in this study. We found that 278 of 439 identified lipid species were significantly altered in AD patients (n = 35) compared to normal controls (n = 32). Notably, most lipid species, including fatty acids, acylcarnitines, cholesteryl ester, ceramides, hexosylceramides, sphingomyelins, lysophosphatidylcholines, lysophosphatidylethanolamines, phosphatidylcholines, phosphatidylinositols, diacylglycerols, and triacylglycerols with total acyl chain carbon number ≥54 and/or total double bond number ≥4 were decreased, whereas phosphatidylethanolamines and triacylglycerols with total double bond number <4 accumulated in AD patients. Besides, the length and unsaturation of acyl chains in triacylglycerols and unsaturation of 1-acyl chain in phosphatidylethanolamines were decreased in AD patients. Moreover, lysophosphatidylcholines were the lipids with the largest alterations, at the center of correlation networks of lipid alterations, and had excellent performances in identifying AD patients. The area under the curve of 1.0 and accuracy rate of 100% could be easily obtained by lysophosphatidylcholine (20:0/0:0) or its combination with lysophosphatidylcholine (17:0/0:0) or lysophosphatidylcholine (20:1/0:0). This study provides novel and comprehensive plasma lipidomic signatures of AD patients, identifies lysophosphatidylcholines as excellent potential biomarkers, and would be beneficial to the pathogenetic study, risk assessment and timely diagnosis and treatment of AD.