BACKGROUND: Increasing evidence from preclinical models has linked the actions of brown adipose tissue (BAT) with protection against atherosclerosis and cardiovascular disease, in part due to its salutary effects on systemic lipid composition. However, human data on the role of BAT in atherosclerosis are scarce. METHODS: In this cross-sectional study, we examined 65 individuals with obesity and analyzed cold-induced BAT activity and vascular inflammation in the aorta using 18 F-fluorodeoxyglucose positron emission tomography combined with computed tomography in combination with systemic lipidomics and proteomics analyses. RESULTS: We identified 21 subjects with cold-induced BAT (BAT positive), whereas 44 individuals had no significant BAT activity (BAT negative) after cold exposure. Both groups had similar age, sex distribution, body mass index, and classical cardiovascular risk profile. However, BAT-positive individuals had significantly less arterial inflammation as evidenced by lower 18 F-fluorodeoxyglucose uptake in the ascending aorta and the aortic arch. Notably, BAT volume, SUV mean , and cold-induced thermogenesis correlated negatively with aortic inflammation, suggesting an atheroprotective role of BAT. Using unbiased lipidomics and proteomics analyses in plasma, we found that anti-inflammatory and potentially antiatherogenic circulating factors, such as cytochrome P450 oxylipin products and the serpin family member SERPINB12, were increased in BAT positive, whereas proatherogenic and prothrombotic factors, including acute phase protein ORM2 (orosomucoid 2), APOD (apolipoprotein D), FGA (fibrinogen A), and FGB (fibrinogen B), were significantly lower in individuals with active BAT. Likewise, the circulating concentrations of inflammatory markers, such as IL-6 (interleukin-6), were reduced in BAT positive versus BAT negative. CONCLUSIONS: Together, these data link human BAT function with protection against arterial inflammation and a potentially antiatherogenic and anti-inflammatory circulating profile. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT02381483 and NCT03168009