BACKGROUND: Neonatal adiposity has many determinants and may be a risk factor for future obesity. Epigenetic regulation of metabolically important genes is a potential contributor. OBJECTIVES: The objective of the study is to determine whether methylation changes in the LEP gene in cord blood DNA are impacted by the maternal environment or affect neonatal adiposity measures. METHODS: A cross-sectional study of 114 full-term neonates born to healthy mothers with normal glucose tolerance was performed. Cord blood was assayed for leptin and genome-wide DNA methylation profiles via the Illumina 450K platform. Neonatal body composition was measured by air displacement plethysmography. Multivariate linear regression models and semi-partial correlation coefficients were used to analyze associations. False discovery rate was estimated to account for multiple comparisons. RESULTS: Maternal pre-pregnancy BMI was associated with decreased methylation at five CpG sites near the LEP transcription start site in an adjusted model (false discovery rate <0.022 for each site). The association between maternal BMI and cord blood leptin approached significance (r = 0.18, p = 0.054). Cord blood leptin was positively correlated with neonatal adiposity measures including birth weight (r = 0.45, p < 0.001), fat mass (r = 0.47, p < 0.001) and percent body fat (r = 0.44, p < 0.001). CONCLUSIONS: Maternal pre-pregnancy BMI is strongly associated with decreased cord blood LEP gene methylation and may mediate the well-known association between maternal pre-pregnancy BMI and neonatal adiposity.