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Background: Pediatric obesity is characterized by an imbalance in pro- and anti-inflammatory markers that are associated with cardiometabolic diseases. Adiponectin (Adpn), an anti-inflammatory marker, is associated with insulin sensitivity, while tumor necrosis factor-alpha (TNFα) has been associated with insulin resistance among youth with obesity. However, it is unknown whether longitudinal changes in Adpn or TNFα predict changes in insulin sensitivity among high-risk youth. Methods: A total of 73 Latino youth with obesity (age 13.3±1.4 y, Female 40.3%, BMIz 2.2±0.3) were enrolled in either a lifestyle intervention or usual care. Given that there were no between-group differences in changes in insulin sensitivity at 6-months, groups were combined for the present analysis. Fasting serum samples were used to measure high-molecular weight Adpn and TNFα before and after intervention. Insulin sensitivity was estimated by the whole-body insulin sensitivity index (WBISI) using insulin and glucose concentrations from a 75-g, 2-h oral glucose tolerance test. Baseline associations were analyzed using Pearson correlations. Linear regression was used to analyze whether changes in Adpn or TNFα predict changes in WBISI, adjusting for age, sex, and intervention assignment. Data from linear regressions are presented as betas (β) and standard errors (SE). Results: At baseline, WBISI was positively and significantly associated with Adpn (r=0.296, p=0.015) but not with TNFα (r=-0.171, p=0.168), adjusting for age and sex. Increases in Adpn were associated with increases in WBISI, whereby for every 1 μg/dL increase in Adpn, there was a 0.7 unit increase in WBISI (SE=0.3, p=0.027). Changes in TNFα did not significantly predict changes in WBISI (β=0.1, SE=0.5, p=0.915). Conclusion: Changes in Adpn but not TNFα were associated with changes in insulin sensitivity following intervention among Latino youth with obesity. Whether Adpn is the mechanism by which health behavior changes increase insulin sensitivity warrants further investigation among high-risk youth populations.