Childhood obesity is a complex disease that is influenced by both genetic and environmental factors. The authors' aim was to determine whether sedentary behavior and physical activity modulate the association between single nucleotide polymorphisms (SNPs) and obesity risk in Chinese children. A population-based study was carried out in 2,848 children (6-18 years of age) in Beijing, China, in 2004. It included 1,229 obese cases and 1,619 normal-weight controls. Lifestyle information was collected through the use of a validated questionnaire, and 6 SNPs were genotyped. The association between the 6 SNPs and obesity risk was modulated by sedentary behavior and physical activity. A higher risk of obesity was observed in children who carried the high-risk alleles of the 6 SNPs and engaged in sedentary behavior ≥2 hours/day outside of school or participated in low or moderate physical activity. Most notably, the association between 5 SNPs (Fas apoptotic inhibitory molecule 2 rs7138803, Niemann-Pick disease, type C1 rs1805081, fat mass- and obesity-associated gene rs6499640, melanocortin 4 receptor gene rs17782313, and brain-derived neurotrophic factor rs6265) and obesity risk was only observed in children who had moderate-to-low physical activity levels or engaged in sedentary behavior, regardless of which risk alleles they carried. The results indicated that encouraging less sedentary behavior and higher levels of physical activity could alleviate the influence of risk alleles on genetic predisposition to childhood obesity, thereby serving as a promising prevention strategy.