The intent of this study was to assess whether the effect of birth weight on later body composition is modified by Pro12Pro, Pro12Ala, and Ala12Ala genotypes of the peroxisome proliferator-activated receptor gamma-2 (PPARgamma-2) gene. The PPARgamma-2 gene polymorphism was genotyped in 273 adolescents aged 13-18.5 y, born at term and whose birth weight was known. They were selected from a cross-sectional multicenter study conducted in five Spanish cities in 2000-2002. Body mass index (BMI) was calculated from weight and height measurements, and body composition and fat distribution were estimated from skinfold thickness. A total of 229 subjects (111 males and 118 females) carried the Pro12Pro genotype and 44 (22 males and 22 females) the Pro12Ala and Ala12Ala PPARgamma-2 genotypes. In the Pro12Pro group, birth weight Z score was positively associated with both fat-free mass (FFM) (p < 0.05) and fat mass (FM) (p < 0.05), but these relationships disappeared after controlling for age, gestational age, socioeconomic status (SES), physical activity, Tanner stage, sex, and BMI. In the Ala12 group, birth weight Z score was positively associated with FFM (p < 0.01), and this relationship remained significant after controlling for confounding variables (p < 0.05). Small body weight at birth may program lower FFM in adolescents carrying the Ala12 allele in the PPARgamma-2 gene.