Background: Metabolomics has provided new insights into mechanistic knowledge of CVD. However, this approach has limited use for studying arterial disease in high-risk women with and without HIV infection. Methods: Using liquid chromatography-tandem mass spectrometry, we profiled plasma levels of 114 cationic polar and 211 nonpolar lipid metabolites among 411 women (72% HIV+; 60% Black and 31% Hispanic) aged 35-50 from the Women’s Interagency HIV Study. Carotid arterial distensibility, a direct measure of carotid stiffness, was calculated from ultrasound measurements of the right common carotid artery diameter at systole and diastole and brachial artery pulse pressure measured. We performed partial least squares discriminant analysis (PLS-DA) to identify metabolite clusters associated with carotid stiffness (lowest vs. the other 3 quartiles of distensibility index). We used multivariate linear regression models to examine associations of individual metabolites with the distensibility index. Results: PLS-DA identified two major metabolite clusters associated with carotid stiffness. In the lipid metabolite cluster, triacylglycerols (TAGs 52:3, 52:4, 54:4), diacylglycerols (DAGs 36:2, 36:3) and sphingomyelins (16:1, 18:1, 18:2) were associated with decreased distensibility, while lysophosphatidylcholines (18:2, 20:5) were associated with increased distensibility. In the cationic polar metabolite cluster, urate, C4-OH carnitine, C5-DC carnitine, pseudouridine and 1-methyladenosine were associated with decreased distensibility. The associations of TAGs 52:3, 52:4, 54:4 and DAG 36:3 with carotid stiffness remained significant after further adjustment for conventional CVD risk factors ( Table ). No interaction by HIV infection was found. Conclusions: Among women with or at risk of HIV infection from predominantly race-ethnic minority groups, plasma TAGs and DAG of higher carbon number and double bond content are associated with carotid stiffness independent of conventional CVD risk factors.