OBJECTIVE: Prospective studies have shown a positive association between leptin concentrations and coronary heart disease (CHD) in men, but its effect in women is unclear. Our objective was to examine the association of serum leptin levels with CHD in a prospective study of women. RESEARCH METHODS AND PROCEDURES: We conducted a prospective (4 year) case (N=165) control (N=335) study nested within a cohort of 4286 British women. RESULTS: With mutual adjustment for each other and age, social class, smoking, and physical activity, leptin was positively associated with BMI, fasting insulin, total cholesterol, low-density lipoprotein-cholesterol, triglycerides, and hypertension and was inversely associated with homeostasis model assessment insulin sensitivity. Leptin was not associated with CHD risk (age-adjusted relative risk for a doubling of leptin: 1.08 [95% confidence interval (CI): 0.91, 1.29]). This changed little with adjustment for childhood and adult social class, smoking, alcohol, and physical activity but attenuated to 1.00 (95% CI: 0.80, 1.26) with further adjustment for other metabolic risk factors (waist-to-hip ratio, low-density lipoprotein-cholesterol, triglycerides, C-reactive protein, fasting insulin, hypertension). DISCUSSION: We found no strong statistical evidence that leptin is associated with CHD risk in this study population of older British women. Further research is needed to compare associations of leptin with CHD in men and women and to determine whether the effect varies by gender.