Objective: Whether the polymorphisms in the UCP3 gene have an influence on plasma homocysteine levels during youth is not known, and to elucidate the putative modifying role of fitness is also of clinical interest. We analysed the association between polymorphisms in the UCP3 gene and plasma homocysteine in youth and to examine whether fitness modifies this association. Methods: The study population comprised 267 Swedish children (8-10 years) and 305 adolescents (14-16 years). Fasting total plasma homocysteine was the outcome variable. We genotyped five UCP3 polymorphisms (rs1800849, rs1800006, rs2075577, rs647126, and rs591758) and oneMTHFR677C>T (rs1801133) polymorphism. Cardiorespiratory fitness was measured with a maximal ergometer bike test. Results: Youth homozygous or heterozygous for the T allele of the rs1800849 polymorphism had significantly higher levels of homocysteine than those carrying the CC genotype (8.56 +/- 4.72 mu mol/L vs. 7.72 +/- 2.73 mu mol/L, respectively, P = 0.011) after adjusting for gender, age, pubertal status, folate and vitamin B(12) intake and MTHFR 677C>T polymorphism, whereas no association was observed for the other analysed polymorphisms. There was a significant interaction effect of fitness x rs1800849 polymorphism (P = 0.042). The effect of the rs1800849 polymorphism on homocysteine levels persisted in youth with low fitness, whereas it was abolished in those with moderate or high cardiorespiratory fitness (P > 0.1). Conclusions: Cardiorespiratory fitness modifies the association between the rs1800849 polymorphism and homocysteine so that the negative effect of the T allele does not persist in youth with moderate to high levels of fitness. (C) 2009 Elsevier Ireland Ltd. All rights reserved.