We examined the associations of two functional variants 866G>A and DEL/INS polymorphisms of UCP2 gene with low-grade inflammatory proteins (C-reactive protein, fibrinogen, complement C3 [C3], and complement C4 [C4]) in 131 children (52.7% boys, aged 9.5 +/- 0.4 y) and 118 adolescents (44.1% males, aged 15.5 +/- 0.4 y) selected from the European Youth Heart Study. Differences in inflammatory markers among the genotype variants of the two UCP2 gene polymorphisms were analyzed after adjusting for sex, age, pubertal stage, fitness, and fatness. The results showed that fibrinogen, C3, and C4 were higher in GG carriers than in subjects carrying the A allele of the 866G>A polymorphism of the UCP2 gene (UCP2 -866G>A) polymorphism (all p < 0.05). The DEL/DEL genotype of 45nt deletion/insertion variant polymorphism of the UCP2 gene (UCP2 DEL/INS) was associated with higher C3 (p < 0.05) than DEL/INS and INS/INS genotypes. This study provides evidence of a role of UCP2 -866G>A in modifying low-grade inflammatory state in apparently healthy children and adolescents. Given the implication of complement factors on atherosclerosis process, these results contribute to explain the reduced cardiovascular risk associated with the A allele of the UCP2 -866G>A polymorphism.