Context and Objective: A growing body of evidence suggests that vitamin D deficiency may adversely affect the cardiovascular system. Therefore, we thought to prospectively assess the association between serum 25-hydroxyvitamin D, the most commonly used index of vitamin D status, and incident coronary heart disease. Design, Setting, and Patients: We measured serum levels of 25[OH]D in 1783 healthy middle-aged subjects (964 men, 819 women) in the population-based Monitoring of Trends and Determinants in Cardiovascular Disease/Cooperative Health Research in the Region of Augsburg studies. A total of 298 coronary heart disease cases were identified over a mean follow-up period of 11 yr. Results: After adjustment for age, survey, and season of blood sampling, the hazard ratio (HR) and 95% confidence interval comparing tertile extremes of serum levels of 25[OH]D was 0.32 (0.16-0.65) (P for trend = 0.001) in women and 0.56 (0.38-0.82) (P for trend = 0.005) in men. Further adjustment for traditional cardiovascular risk factors slightly attenuated the association in women [HR 0.39 (0.18-0.84); P for trend = 0.013], whereas it became nonsignificant in men [HR 0.76 (0.49-1.17); P for trend = 0.215]. After additional adjustment for C-reactive protein, IL-6, soluble intercellular adhesion molecule-1, and interferon-γ-inducible protein-10, the association still remained significant in women [HR 0.42 (0.19-0.93); P for trend = 0.028], and it was further reduced in men [HR 0.84 (0.52-1.35); P for trend = 0.461]. Conclusion: Our findings suggest that higher vitamin D levels are associated with decreased risk of coronary heart disease. This effect is more pronounced in women than in men. Further clinical and experimental studies are needed to investigate the sex differences and whether vitamin D supplementation could contribute to the prevention of coronary heart disease.