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The mechanisms linking body mass index to cardiovascular disease are still not clearly defined. The purpose of this study was to find out how much of the effect of central and general adiposity on cardiovascular disease is mediated through blood pressure, cholesterol, and glucose, and how much is independent of these factors.The study population included participants, aged ≥30 years, free of cardiovascular disease at baseline with median follow-up of 13.9 years. The total effects were broken down into natural direct and indirect effects using the inverse odds weighting method in the context of survival models. Systolic blood pressure, total serum cholesterol, and fasting plasma glucose as the primary measure of blood glucose were used as mediators. Blood pressure and cholesterol with indirect hazard ratios of 1.09 (95% confidence interval: 1.006–1.18) and 1.35 (95% confidence interval: 1.12–1.62) were the most important mediators for overweight-cardiovascular disease and obesity-cardiovascular disease relationships, respectively. The proportion mediated of overweight was 22% (6–47%) for blood pressure, 18% (5–37%) for blood glucose, and 20% (7–43%) for cholesterol. The same measure for obesity was 65% (35–91%) for cholesterol. For central adiposity, blood pressure, glucose, and cholesterol were the most important mediators with proportion mediated of 36% (17–72%), 23% (9–48%), and 21% (8–45%), respectively.The findings of this study show that proper control of cardiometabolic risk factors of blood pressure, blood glucose, and dyslipidemia in an adult population can be effective to significantly reduce the effects of general and abdominal adiposity on cardiovascular diseases.