ABSTRACT Background There is growing recognition that recent global increases in obesity are the product of a complex interplay between genetic and environmental factors. However, in gene-environment studies of obesity, ‘environment’ usually refers to individual behavioural factors that influence energy balance, while more upstream environmental factors are overlooked. We examined gene-environment interactions between genetic risk of obesity and two neighbourhood characteristics likely to be associated with obesity (proximity to takeaway/fast-food outlets and availability of physical activity facilities). Methods We used data from 335,046 adults aged 40-70 in the UK Biobank cohort to conduct a population-based cross-sectional study of interactions between neighbourhood characteristics and genetic risk of obesity, in relation to BMI. Proximity to a fast-food outlet was defined as distance from home address to nearest takeaway/fast-food outlet, and availability of physical activity facilities as the number of formal physical activity facilities within one kilometre of home address. Genetic risk of obesity was operationalised by 91-SNP and 69-SNP weighted genetic risk scores, and by six individual SNPs considered separately. Multivariable, mixed effects models with product terms for the gene-environment interactions were estimated. Results After accounting for likely confounding, the association between proximity to takeaway/fast-food outlets and BMI was stronger among those at increased genetic risk of obesity, with evidence of an interaction with polygenic risk scores (P=0.018 and P=0.028 for 69-SNP and 91-SNP scores, respectively) and in particular with a SNP linked to MC4R (P=0.009), a gene known to regulate food intake. We found very little evidence of a gene-environment interaction for availability of physical activity facilities. Conclusions Individuals at an increased genetic risk of obesity may be more sensitive to exposure to the local fast-food environment. Ensuring that neighbourhood residential environments are designed to promote a healthy weight may be particularly important for those with greater genetic susceptibility to obesity.