In-utero exposures through adverse fetal programming are emerging as an important contributing factor to the epidemic of childhood obesity. This study examines the impact of in-utero exposure to caffeine on the risk of childhood obesity in offspring. A prospective study of pregnant women with 15 years follow-up of their offspring was conducted to examine the impact of in-utero exposure to caffeine on the risk of childhood obesity. Maternal caffeine intake was prospectively ascertained during pregnancy and outcome measures (body mass index (BMI)) were ascertained from medical charts, with 17 BMI measurements per child, on average, during the follow-up period. Potential confounders including known perinatal risk factors for childhood obesity were adjusted for using the generalized estimating equations model with repeated measurements. After controlling for potential confounders, compared with those without caffeine exposure, in-utero exposure to caffeine overall is associated with 87% increased risk of childhood obesity: odds ratio (OR) =1.87, 95% confidence interval (CI): 1.12-3.12. This association demonstrated a dose-response relationship: OR=1.77 (1.05-3.00) for maternal daily caffeine intake <150?mg per day, OR=2.37 (1.24-4.52) for caffeine intake ?150?mg per day during pregnancy, respectively. We also observed a linear relationship: every one unit increase (log10 scale) in the amount of maternal caffeine intake was associated with 23% increased risk of obesity in offspring. The dose-response relationship appears stronger for persistent obesity than for transitory obesity (occasional high BMI), and for girls than for boys. We observed an association of in-utero exposure to caffeine with increased risk of childhood obesity. If this observation is further replicated in other studies, the finding will contribute to the understanding of fetal programming of childhood diseases and development of intervention strategy to prevent childhood obesity.