Background Family history of coronary heart disease ( CHD ) as well as genetic predisposition to CHD assessed by a genetic risk score ( GRS ) are predictors of CHD risk. It is, however, uncertain to what extent these risk predictors are mediated by major metabolic pathways. Methods and Results Total effects of self‐reported family history and a 50‐variant GRS ( GRS 50), as well as effects mediated by apolipoprotein B and A‐I (apoB, apoA‐I), blood pressure, and diabetes mellitus, on incidence of CHD were estimated in 23 595 participants of the Malmö Diet and Cancer study (a prospective, population‐based study). During a median follow‐up of 14.4 years, 2213 participants experienced a first CHD event. Family history of CHD and GRS 50 (highest versus other quintiles) were associated with incident CHD , with hazard ratios of 1.52 (95% CI : 1.39–1.65) and 1.53 (95% CI : 1.39–1.68), respectively, after adjusting for age, sex, and smoking status. Small proportions of the family history effect were mediated by metabolic risk factors: 8.3% (95% CI : 5.8–11.7%) by the apoB pathway, 1.7% (95% CI : 0.2–3.4%) by apoA‐I, 8.5% (95% CI : 5.9–12.0%) by blood pressure, and 1.5% (95% CI : −0.8% to 3.8%) by diabetes mellitus. Similarly, small proportions of GRS 50 were mediated: 8.1% (95% CI : 5.5–11.8%) by apoB, 1.2% (95% CI : 0.5–3.0%) by apoA‐I, 4.2% (95% CI : 1.3–7.5%) by blood pressure, and −0.9% (95% CI : −3.7% to 1.6%) by diabetes mellitus. Conclusions A fraction of the CHD risk associated with family history or with GRS 50 is mediated through elevated blood lipids and hypertension, but not through diabetes mellitus. However, a major part (≥80%) of the genetic effect operates independently of established metabolic risk factor pathways.