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<b>Background:</b> Atherosclerosis and its associated chronic inflammation of the arterial wall disrupt fatty acid metabolism, leading to changes in plasma fatty acid composition. These alterations can be used to improve disease diagnosis and risk stratification by the development and application of specific lipidomic indices. <b>Objectives:</b> The objectives of this study are to evaluate the performance of conventional fatty acid indices and enhance diagnostic efficiency in atherosclerosis by introducing novel index based on plasma PUFA n-6 and n-3 content (Omega-6/3 Balance Index, O6/3-BI), as well as the perspective SFA/MUFA ratio (stearic/oleic acid ratio, C18:0/C18:1n-9) and a logit function combining PUFA and SFA/MUFA biomarkers. <b>Methods:</b> Plasma fatty acids were quantified by LC-MS/MS in healthy controls (<i>n</i> = 50) and patients with carotid atherosclerosis (<i>n</i> = 52), stratified by atorvastatin, rosuvastatin, or no statin therapy. The conventional indices (the Omega-3 Status (EPA + DHA), AA/EPA, and the omega-6/omega-3 ratio), and pathway ratios (C18:0/C18:1n-9; and C20:4n-6/C22:4n-6), as well as the newly introduced PUFA index and combined PUFA-SFA/MUFA logit function, were calculated. Their diagnostic performance for distinguishing atherosclerosis was assessed by a receiver operating characteristic (ROC) analysis with the cross-validation and calculation of Cliff's Δ effect size. <b>Results:</b> The conventional parameters demonstrated a poor to low discrimination ability of the atherosclerosis patients' groups from healthy controls (area under the ROC curve, AUC 0.548-0.711). In statin-treated patients, these conventional markers lost significance. The newly introduced PUFA index and SFA/MUFA ratio demonstrated improved patients' discrimination with AUC 0.734-0.780 for the former and strong predictive power with AUC 0.831-0.858 for the latter marker and maintained their diagnostic value under statin therapy. The most significant positive effect size was observed for the SFA/MUFA ratio with Cliff's Δ = 0.67-0.71. The combined PUFA-SFA/MUFA logit function also demonstrated a strong predictive power with AUC = 0.880 (Cliff's Δ = -0.76), outperforming any single index. <b>Conclusions:</b> The newly introduced lipidomic index based on the PUFA content, SFA/MUFA ratio, and a logit function combining PUFA-SFA/MUFA biomarkers demonstrated a substantially better discrimination of atherosclerosis-related fatty acid metabolic disturbances than conventional fatty acid biomarkers.