SummaryBackgroundEvidence indicates that the adverse health effects of obesity differ between genetically and environmentally influenced obesity. We examined differences in the association between obesity and cardiovascular disease (CVD) between individuals with a genetically predicted low, medium, or high body mass index (BMI).MethodsWe used cohort data from Swedish twins born before 1959 who had BMI measured between the ages of 40–64 years (midlife) or at the age of 65 years or later (late-life), or both, and prospective CVD information from nationwide register linkage through 2016. A polygenic score for BMI (PGSBMI) was used to define genetically predicted BMI. Individuals missing BMI or covariate data, or diagnosed with CVD at first BMI measure, were excluded, leaving an analysis sample of 17,988 individuals. We applied Cox proportional hazard models to examine the association between BMI category and incident CVD, stratified by the PGSBMI. Co-twin control models were applied to adjust for genetic influences not captured by the PGSBMI.FindingsBetween 1984 and 2010, the 17,988 participants were enrolled in sub-studies of the Swedish Twin Registry. Midlife obesity was associated with a higher risk of CVD across all PGSBMIcategories, but the association was stronger with genetically predicted lower BMI (hazard ratio from 1.55 to 2.08 for those with high and low PGSBMI, respectively). Within monozygotic twin pairs, the association did not differ by genetically predicted BMI, indicating genetic confounding not captured by the PGSBMI. Results were similar when obesity was measured in late-life, but suffered from low power.InterpretationObesity was associated with CVD regardless of PGSBMIcategory, but obesity influenced by genetic predisposition (genetically predicted high BMI) was less harmful than obesity influenced by environmental factors (obesity despite genetically predicted low BMI). However, additional genetic factors, not captured by the PGSBMI, still influence the associations.FundingTheStrategic Research Program in Epidemiology at Karolinska Institutet;Loo and Hans Osterman’s Foundation;Foundation for Geriatric Diseases at Karolinska Institutet; theSwedish Research Council for Health,Working Life and Welfare; the10.13039/501100004359Swedish Research Council; and the10.13039/100000002National Institutes of Health.