ObjectivesChildhood obesity is a growing health problem and requires a tailored treatment. This study explored the sex differences in cardiovascular risk factors in children/adolescents with obesity and in response to a weight loss intervention.MethodsFive hundred and thirty-three children/adolescents with obesity and their parents underwent to a 3-months lifestyle intervention program. Tanner criteria were used to assess the pubertal stage. Before and after 3 months, anthropometric measurements, blood pressure (BP), and biochemical measurements were assessed.ResultsFour hundred and forty five participants completed the treatment (age 12.4 ± 2.7 years, males 45.8%, prepubertal 29.2%, BMI z score 2.3 ± 0.2). In comparison to boys, prepubertal girls had higher values of BMI z score (2.4 ± 02 vs. 2.3 ± 0.2, p < 0.05), waist circumference z score (2.2 ± 0.3 vs. 2.0 ± 0.3, p < 0.05), HOMA-IR [2.9 (2.1–4.9) vs. 2.3(1.5–3.6), p < 0.01], prevalence of hypertransaminasemia (41.3% vs. 17.7%, p < 0.05) and lower levels of HDL cholesterol (46.2 ± 9.8 vs. 51.2 ± 10.5 mg/dl, p < 0.05). In the pubertal stage, boys had worse cardiometabolic risk profile than girls, including unfavourable measure of systolic BP (z score: 0.6 ± 1.0 vs. 0.3 ± 1.0, p < 0.01), fasting glucose (87.2 ± 6.1 vs. 84.8 ± 7.7 mg/dl, p < 0.01), ALT (26.9 ± 21.5 vs. 20.2 ± 10.6 U/L, p < 0.001) and uric acid (6.1 ± 1.9 vs. 5.0 ± 1.0 mg/dl, p < 0.001). After the lifestyle intervention, changes in BMI z score (p < 0.05) were higher in pubertal boys than pubertal girls. The systolic blood pressure decrease was greater in pubertal boys than in their female counterpart (Δ systolic BP: −7.2 mmHg in boys vs. −3.6 mmHg in girls, p < 0.05; Δ systolic BP z score: −0.6 in boys vs. −0.3 in girls, p < 0.05). LDL cholesterol showed an improvement only in boys, and ALT in the whole group.ConclusionOur study showed that a short-term lifestyle intervention is more effective in reducing BMI z score and cardiovascular risk factors in pubertal boys than in their female counterparts. Further investigation is needed to deepen this gender difference, especially to develop a tailor-made intervention.