Background Colorectal advanced adenoma (CAA) is a key precancerous lesion of colorectal cancer (CRC), and early diagnosis can lessen CRC morbidity and mortality. Although abnormal lipid metabolism is associated with the development of CRC, there are no studies on the biomarkers and mechanisms of lipid metabolism linked to CAA carcinogenesis. Methods: The serum lipidomics was investigated with CAA (N = 46) and CRC (N = 50) patients by ultra high-performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) in both electrospray ionization (ESI) modes. Differential lipids were selected by univariate and multivariate statistics analysis, and their diagnostic performance was evaluated using a receiver operating characteristic curve (ROC) analysis. Results Combining P 1, 59 differential lipids were obtained totally. Ten of them showed good discriminant ability for CAA and CRC (AUC > 0.900). Especially, the lipid panel consisting of PC 44:5, PC 35:6e, and SM d40:3 showed the highest selection frequency and outperformed (AUC = 0.952). Additionally, phosphatidylcholine (PC) and sphingomyelin (SM) were the main differential and high-performance lipids. Conclusions PC and SM are the main biomarker candidates to distinguish CAA from CRC, and dysregulated metabolism of them may play a key role in CAA carcinogenesis.