The causal relation of total Homocysteine (tHcy) to coronary heart diseases (CHD) is unclear. In vitro studies suggest a proinflammatory effect. Among 32,826 women from the Nurses' Health Study who provided blood samples in 1989-1990, 237 CHD events were documented during 8 years of follow-up. The cases (1:2) were matched to controls on age, smoking, and month of blood draw. Plasma tHcy was inversely associated with blood levels of folate (partial r = -0.3, P < 0.0001) and B1(2) (r = -0.2, P < 0.0001) and with dietary intake of folate (r = -0.1, P < 0.01) and B(2) vitamin (r = -0.1, P = 0.01). tHcy was positively associated with soluble tumor necrosis receptor (sTNF-R) 1 and 2 (partial r = 0.2, P < 0.0001). In a multivariate model adjusted for age, smoking, BMI, parental history, hypertension, diabetes, postmenopausal hormone use, physical activity and alcohol intake, the relative risk of CHD between the extreme quartiles of tHcy was 1.66 (95% CI; 1.05-2.64, P trend = 0.02). The association was not appreciably attenuated after further adjustments for sTNF-R1, sTNF-R2, CRP, or Total Cholesterol:/HDL-c ratio. tHcy is an independent risk predictor of CHD and modestly associated with TNF-receptors. However, the inflammatory biomarkers measured could not explain its role in CHD.