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 γ-2 (PPARγ-2) gene. The PPARγ-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 PPARγ-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 PPARγ-2 gene.Abbreviations: FFM, fat-free mass; FM, fat mass; PPARγ-2, peroxisome proliferator–activated receptor γ-2