Leptin can be considered as a peripheral signal which informs the centers about the mass of energy stores. Studies done on the human adult population have demonstrated that degree of adiposity and insulin levels play a major role as determinants of leptin circulating levels. The aim of this study was to evaluate which factors may influence leptin levels at birth. We examined the role played by baby size and by the metabolic environment the fetus was exposed to during pregnancy. We considered 85 newborns from normal (n = 60), gestational (GDM, n = 17) and pregestational (IDDM = 8) diabetes mellitus mothers. At delivery, blood was taken from the umbilical cord vein. Babies from normal and GDM mothers were subdivided into AGA (appropriate for gestational age) and LGA (large for gestational age). There was no difference in leptin levels between babies from normal or GDM mothers belonging to the same weight category, but leptin levels were always higher in LGA than in AGA newborns, and highly correlated with birth weight (r = 0.34, P = 0.001). Moreover, IDDM mothers gave birth to newborns with significantly higher levels of leptin and insulin when compared with normal and GDM mothers. Diabetes of both GDM and IDDM mothers was clinically well controlled (HbA1c was 4.0 and 7.2, respectively). The correlation between leptin and insulin was significant only when newborns from IDDM mothers were included in the regression analysis (r = 0.39, P = 0.0002). Our results suggest that degree of adiposity is one of the main regulators of leptin concentration in the human newborn and that babies exposed to an altered, though clinically controlled, metabolic environment, as in IDDM mothers, have increased levels of leptin.