ABSTRACT: OBJECTIVES:Leptin is a hormone produced by adipose tissue that promotes satiety, and some evidence suggests that greater early life leptin exposure prevents excessive adiposity gain in later life. However, few studies have analyzed dynamic changes in leptin throughout childhood in relation to later cardio-metabolic health. Our study aims to identify distinct leptin trajectories in childhood, and to examine their associations with cardio-metabolic outcomes in adolescence. METHODS:Among children in the Project Viva cohort born 1999-2002 in Massachusetts, we used latent class growth models to identify leptin trajectories independent of maternal BMI, child sex, race/ethnicity, size at birth and current age and size among 1360 children with leptin measured at least once at birth, early childhood (mean 3.3?±?SD 0.3?years), or mid-childhood (7.9?±?0.8?years). At research visits in early adolescence (13.2?±?0.9?years), we assessed cardio-metabolic outcomes including adiposity measures, fasting biomarkers, and blood pressure among 855 children. We then applied multiple regression models to examine associations of the leptin trajectories with these cardio-metabolic outcomes in early adolescence, adjusting for child age at outcome, maternal age, education, prenatal smoking and glucose, total gestational weight gain and paternal BMI. RESULTS:The latent class growth model identified 3 distinct leptin trajectories: "low stable" (n?=?1031, 75.8%), "high-decreasing" (n?=?219, 16.1%) and "intermediate-increasing" (n?=?110, 8.1%). In adjusted models, the intermediate-increasing leptin trajectory was associated with higher early adolescence adiposity measures (e.g. BMI z-score: 0.62?units; 95% confidence interval: 0.28, 0.96 and odds of obesity: 2.84: 1.17, 6.94), but lower systolic blood pressure (-0.46 z-score units; -0.74, -0.18), compared to the low-stable group. CONCLUSIONS:Our findings on leptin trajectories in childhood suggest important differences and associations with later metabolic outcomes.