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Background: Lipid metabolism disruption and excess cardiovascular disease (CVD) risk have been associated with HIV infection, yet plasma lipidomics profile and its relationship with CVD risk has been rarely examined in HIV-infected individuals.Methods: Using liquid chromatography tandem mass spectrometry, 211 plasma lipid species from 13 classes were profiled in 737 women and men aged 35-55 years (520 HIV+, 217 HIV-) from the Women’s Interagency HIV Study and the Multicenter AIDS Cohort Study. Repeated B-mode carotid artery ultrasound imaging was obtained in 2004-2013. Poisson regression and network analysis were used to examine associations of baseline lipids with incident carotid plaque over 7 years (112 cases, 90 HIV+ and 22 HIV-).Results: Adjusted for demographic and behavioral factors, 120 individual species from 11 lipid classes showed significant associations with incident carotid plaque (all P<0.05 FDR adjusted). The risk ratios were 1.22 to 1.44 per standard deviation increment for top significant lipids from 11 classes. Further adjustment for HIV serostatus and conventional CVD risk factors did not change the results. No evidence of effect modification by HIV serostatus was observed. Network analysis identified 2 lipid modules (Blue and Pink), which included triacylglycerols (TAGs) and phosphatidylcholines of higher acyl carbon number and greater double bond content, showing the strongest associations with incident carotid plaque (Figure). Of note, the Blue module, but not the Pink module, also showed a strong positive association with HIV infection. Most lipids in the Blue module had higher levels in HIV+ compared to HIV- individuals, and were associated with increased risk of carotid plaque (Figure).Conclusions: Lipidomics profiling identified that multiple lipids, especially, TAGs, are increased in HIV infection and associated with progression of atherosclerosis. Our data provide new insights into early lipid metabolism alterations preceding the development of CVD in HIV infection.