This study tested whether the plasma level of total homocysteine (tHcy) was predictive of obstructive coronary artery disease (CAD) and clinical outcome in patients undergoing coronary angiographic (CAG) study. From September 2002 to October 2004, 1,305 consecutive patients with angina pectoris undergoing CAG study were consecutively enrolled. Blood samples were prospectively collected to assess the plasma level of tHcy from each patient before catheterization. Of these 1305 patients, 676 (51.8%) had multivessel disease (group 1), 367 (28.1%) had single-vessel disease (group 2), and 262 (20.1%) had normal coronary artery or insignificant coronary artery disease (group 3). The plasma level of tHcy was notably higher in group 1 than in groups 2 and 3 (11.6 ± 4.4 versus 10.9 ± 4.0 versus 10.4 ± 3.8, P < 0.001). Univariate binary logistic regression analysis demonstrated that the plasma tHcy level was strongly associated with multiple-vessel disease (MVD) (defined as ≥ 2 vessel disease) (P < 0.001). Multivariate binary logistic regression analysis showed that tHcy level, fasting blood sugar, diabetes mellitus, and age were significantly and independently predictive of MVD (all P < 0.03). Univariate Cox regression analysis demonstrated that tHcy level was predictive of long-term mortality (P = 0.042). However, the tHcy level was not an independent predictor of long-term mortality on multivariate Cox regression analysis (P > 0.05). The results of our study support the hypothesis that tHcy level is an independent predictor of MVD in patients with chest pain undergoing CAG study. Conversely, our study did not support the tHcy level as an independent predictor of long-term mortality in this clinical setting.