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Introduction: Altered acylcarnitine concentrations may reflect impaired mitochondrial metabolism and are implicated in cardiovascular disease (CVD). Disturbances in carnitine metabolism have been observed in HIV infection, but it is unknown whether this is related to CVD risk in HIV infected people.Methods: Twenty-six acylcarnitine species were profiled with ultrahigh-performance liquid chromatography/tandem mass spectrometry in 705 men and women with or at risk of HIV infection in the Multicenter AIDS Cohort Study and the Women’s Interagency HIV Study. Using a weighted score approach to define aggregate levels of plasma acylcarnitines, we assessed the associations of short-chain (C2-C7), medium-chain (C8-C14) and long-chain acylcarnitine (C16-C26) with incident carotid plaque, over 7-year follow-up, defined as a carotid artery region with focal intima-media thickness>1.5mm among those with no baseline carotid plaque.Results: The mean age was 45 years and 70% were non-white. The majority (70%) had HIV, and 68% of 394 participants on antiretroviral therapy (ART) had undetectable HIV viral load. Over 7 years, 108 participants developed carotid plaque. Comparing HIV-infected with HIV-uninfected participants, some individual acylcarnitines were higher (C3, C16, C20, C26) while others were lower (C8, C10, C20:4) (all P<0.05), but no significant differences were found in aggregate levels of short-chain, medium-chain, or long-chain acylcarnitines. After adjusted for demographic, behavioral, and HIV infection related factors (HIV serostatus, CD4 cell count and ART), plasma levels of short-chain (risk ratio [RR] = 1.26 [95% CI 1.06-1.50] per standard deviation increment; P=0.008), medium-chain(RR=1.20 [1.01-1.43]; P=0.04) and long-chain acylcarnitines (RR=1.18 [1.00-1.40]; P=0.05) were associated with increased risk of carotid plaque. After further adjusting for traditional CVD risk factors (BMI, total- and HDL-cholesterol, blood pressure, lipid-lowering medication and antihypertensive medication use), the association of short-chain acylcarnitines, but not medium-chain or long-chain acylcarnitines, with carotid plaque remained significant (RR=1.23 [1.04-1.46]; P=0.01). Results were consistent between men and women. Further analyses indicated that the association of short-chain acylcarnitines and carotid plaque was stronger in individuals with HIV infection (RR=1.29 [1.08-1.54]) than those without HIV infection (RR=0.98 [0.66-1.45]), and stronger among HIV+ individuals with detectable viral load (RR =1.42 [1.15-1.75]) than those who had continuous virus suppression (RR =1.02 [0.71-1.47]).Conclusion: Plasma short-chain acylcarnitines were associated with increased risk of carotid plaque formation, independent of traditional CVD risk factors, especially in HIV-infected individuals and those with poor control of HIV viral load.