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We examined associations of 5 plasma choline metabolites with carotid plaque among 520 HIV-infected and 217 HIV-uninfected participants (112 incident plaque cases) over 7 years. After multivariable adjustment, higher gut microbiota-related metabolite trimethylamine- N -oxide (TMAO) was associated with an increased risk of carotid plaque in HIV-infected participants (risk ratio = 1.25 per standard deviation increment; 95% confidence interval, 1.05–1.50; P =.01). TMAO was positively correlated with biomarkers of monocyte activation and inflammation (sCD14, sCD163). Further adjustment for these biomarkers attenuated the association between TMAO and carotid plaque (P =.08). Among HIV-infected individuals, plasma TMAO was associated with carotid atherosclerosis progression, partially through immune activation and inflammation. [ABSTRACT FROM AUTHOR]