BACKGROUND: While both adipose tissue accumulation and tryptophan metabolism alterations are features of human immunodeficiency virus (HIV) infection, their interplay is unclear. We investigated associations between abdominal adipose tissue, alterations in kynurenine pathway of tryptophan metabolism, and systemic inflammation in people with HIV (PWH). METHODS: Eight hundred sixty-four PWH and 75 uninfected controls were included. Plasma samples were collected and analyzed for kynurenine metabolites, neopterin, high-sensitivity C-reactive protein (hs-CRP), and lipids. Regression models were used to test associations in PWH. RESULTS: PWH had higher kynurenine-to-tryptophan ratio than uninfected individuals (P < .001). In PWH, increase in waist-to-hip ratio was associated with higher kynurenine-to-tryptophan ratio (P = .009) and quinolinic-to-kynurenic acid ratio (P = .006) and lower kynurenic acid concentration (P = .019). Quinolinic-to-kynurenic acid ratio was associated with higher hs-CRP (P < .001) and neopterin concentrations (P < .001), while kynurenic acid was associated with lower hs-CRP (P = .025) and neopterin concentrations (P = .034). CONCLUSIONS: In PWH, increase in abdominal adipose tissue was associated with increased quinolinic-to-kynurenic acid ratio, suggesting activation of proinflammatory pathway of kynurenine metabolism, with reduction of anti-inflammatory molecules and increase in systemic inflammation. Our results suggest dysregulation of kynurenine metabolism associated with abdominal fat accumulation to be a potential source of inflammation in HIV infection.