Homocysteine is associated with coronary disease (CAD). However, the strength of the association after accounting for traditional and emerging risk factors is unclear, particularly since flour fortification with folate was mandated in the USA. We analyzed the association between traditional and emerging risk factors and CAD in 504 patients undergoing clinically-indicated angiography between July 1998 and January 1999. Significant CAD (> or =50% stenosis in > or =1 artery) was present in 271 patients (54%). Mean homocysteine (micromol/l) was 9.36+/-3.07; hyperhomocysteinemia (>13 micromol/l) was present in 7.9% of patients. Mean homocysteine was 9.29+/-3.02 in patients with no disease (no stenoses or stenoses <10%), 9.09+/-2.47 in patients with mild disease (stenoses 10-50%), 9.12+/-2.39 in patients with one vessel disease (VD) (>50% stenosis in one coronary artery), 9.28+/-3.19 in patients with two VD, and 10.1+/-3.89 in patients with three VD (P=0.0793). Multivariate analysis that included age, gender, smoking, LDL, HDL, Lp(a), apo A1, and apo B revealed no independent association between quartile of homocysteine and odds ratio (OR) for CAD. In summary, we found no association between homocysteine and CAD on angiography. The homocysteine-lowering effect of folate-fortified flour, or the inclusion of many traditional and emerging risk factors in multivariate analysis, are potential explanations.