Rationale: Obesity leads to increased ischemic heart disease (IHD) risk, but the risk is thought to be mediated through intermediate variables and may not be caused by increased weight per se. Objective: To test the hypothesis that the increased IHD risk due to obesity is mediated through lipoproteins, blood pressure, glucose, and/or C-reactive protein. Methods and Results: ~90,000 participants from Copenhagen were included in a Mendelian randomization design with mediation analyses. Associations were examined using conventional measurements of body mass index (BMI) and intermediate variables, and using genetic variants associated with these. During up to 22 years of follow-up 13,945 participants developed IHD. The increased IHD risk due to obesity was partly mediated through elevated levels of nonfasting remnant cholesterol and low-density lipoprotein(LDL) cholesterol, through elevated blood pressure, and possibly also through elevated nonfasting glucose levels; however, reduced high-density lipoprotein cholesterol and elevated C-reactive protein levels were not mediators in genetic analyses. The three intermediate variables that explained the highest excess risk of IHD from genetically determined obesity were LDL cholesterol with 8%, systolic blood pressure with 7%, and remnant cholesterol with 7% excess risk of IHD. Corresponding observational excess risks using conventional BMI were 21%, 11%, and 20%, respectively. Conclusions: The increased IHD risk due to obesity was partly mediated through elevated levels of nonfasting remnant and LDL cholesterol, and through elevated blood pressure. Our results suggest there may be benefit to gain by reducing levels of these risk factors in obese individuals not able to achieve sustained weight loss.