Background: Obesity is a multifactorial condition influenced by genetics, lifestyle, and environment. Objective: We investigated whether the association of a validated genetic profile risk score for obesity (GPRS-obesity) with body mass index (BMI) and waist circumference (WC) was modified by sleep characteristics. Design: This study included cross-sectional data from 119,859 white European adults, aged 37-73 y, participating in the UK Biobank. Interactions of GPRS-obesity and sleep characteristics (sleep duration, chronotype, day napping, and shift work) with their effects on BMI and WC were investigated. Results: beta Values are expressed as the change in BMI (in kg/m(2)) or WC per 1-SD increase in GPRS-obesity. The GPRS-obesity was associated with BMI (beta: 0.57; 95% CI: 0.55, 0.60; P = 6.3 x 10(-2207)) and WC (1.21 cm; 95% CI: 1.15, 1.28 cm; P = 4.2 x 10(-2289)). There were significant interactions of GPRS-obesity and a variety of sleep characteristics with their relation with BMI (P-interaction, 0.05). In participants who slept,7 or >9 h daily, the effect of GPRS-obesity on BMI was stronger (beta: 0.60; 95% CI: 0.54, 0.65 and b: 0.73; 95% CI: 0.49, 0.97, respectively) than in normal-length sleepers (7-9 h; beta: 0.52; 95% CI: 0.49, 0.55). A similar pattern was observed for shift workers (beta: 0.68; 95% CI: 0.59, 0.77 compared with beta: 0.54; 95% CI: 0.51, 0.58 for non-shift workers) and for night-shift workers (beta: 0.69; 95% CI: 0.56, 0.82 compared with beta: 0.55; 95% CI: 0.51, 0.58 for non-night-shift workers), for those taking naps during the day (beta: 0.65; 95% CI: 0.52, 0.78 compared with beta: 0.51; 95% CI: 0.48, 0.55 for those who never or rarely had naps), and for those with a self-reported evening chronotype (beta: 0.72; 95% CI: 0.61, 0.82 compared with beta: 0.52; 95% CI: 0.47, 0.57 for morning chronotype). Similar findings were obtained by using WC as the outcome. Conclusion: This study shows that the association between genetic risk for obesity and phenotypic adiposity measures is exacerbated by adverse sleeping characteristics.