Individuals with Down syndrome have been generally described as having high levels of oxidative stress, which have been associated to an increased morbidity. Fortunately, recent studies have reported that aerobic training may upregulate antioxidant defence system both in general population and individuals with trisomy 21. Accordingly, the present study was conducted to ascertain the effectiveness of aerobic training in reducing protein oxidation. To achieve this goal, 31 adolescents with Down syndrome performed a 12-week training program on a treadmill with 3 days/week, consisting of warm-up (15 min), main part (20–35 min) at a work intensity of 60–75% of peak heart rate (HRmax=194.5–[0.56 age]) and cool-down (10 min). A control group included seven age-, sex- and BMI-matched adolescents with trisomy 21 that did not perform any training program. Plasma carbonyl content was determined by means of a slightly modified Levine method. Pre- and post-training carbonyl contents were 1.98±0.2 [95% confidence intervals (95% CI): 1.94–2.02] nmol/mg protein and 1.16±0.1 (95% CI: 1.14–1.18) nmol/mg protein, respectively. When compared with baseline values, it was decreased significantly (1.98±0.2 vs 1.16±0.1; P<0.001). It was concluded that 12-week exercise program significantly reduced protein oxidation in adolescents with Down syndrome. Further long-term follow-up studies are required to determine whether correction of this oxidant imbalance improves clinical outcomes of individuals with trisomy 21.