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An acute bout of endurance exercise in adults stimulates a same-day anti-inflammatory response which may affect low-grade chronic inflammation and insulin resistance and benefit cardio-metabolic health. The anti-inflammatory responses to intermittent games-based exercise and to exercise in young people beyond 2 hours post-exercise are unknown. Thus, the purpose of the present study is to examine the anti-inflammatory, glycemic and insulinemic response to games-based activity in adolescents. Following ethical approval and familiarization, 39 adolescents (12.3 ± 0.7 years) completed an exercise (E) and rested (R) trial in a counterbalanced, randomized crossover design. Following a standardized breakfast, participants completed 1-hour games-based activity. Capillary blood samples were taken at baseline, immediately and 1 hour post-exercise, and 30, 60 and 120 minutes following a standardized lunch. A final blood sample was taken the next morning. Data were analyzed using repeated measures ANOVA. IL-6 concentration was higher on day one of the exercise trial (E:3.4 ± 0.4, R:2.7 ± 0.4 pg/mL; P = 0.006), as was the anti-inflammatory IL-6:TNF-α ratio (E:5.53 ± 0.93, R:3.75 ± 0.45; P = 0.027). Levels of the anti-inflammatory cytokine IL-10 increased on day two of the exercise trial (E:2.11 ± 0.23, R:1.66 ± 0.16 pg/mL; P = 0.032). Insulin sensitivity was enhanced on the exercise trial with a reduction in iAUC following the standardized lunch (E:2310 ± 834, R:3122 ± 1443 mU/L × 120 minutes; P < 0.001). Games-based activity stimulated an anti-inflammatory response up to 24 hours post-exercise and improved insulin sensitivity in response to a standardized meal in healthy adolescents. These novel findings suggest that games-based activity is an ecologically valid mode of exercise to elicit beneficial effects on cardio-metabolic risk factors in young people., (© 2018 The Authors. Scandinavian Journal of Medicine & Science In Sports Published by John Wiley & Sons Ltd.)