To examine the graded risks for coronary artery disease (CAD) associated with plasma homocyst(e)ine [H(e)] and to evaluate the extent to which this risk is mediated by altered vitamin status, we measured plasma concentrations of H(e), vitamins B6 and B12, and folate as well as other coronary risk factors in subjects with early familial CAD and in control subjects. We studied 120 male and 42 female patients with early CAD who were unrelated to each other but were from families in which at least one other sibling had early CAD. Control subjects were 85 men and 70 women with the same age range (38 to 68) as the subjects with CAD at screening. Increasing H(e) was associated with graded increased risks of CAD that appeared consistent with a multiplicative model. Relative odds for CAD were approximately 12.8 in women when those with H(e) levels of 9 mumol/L and above were compared with those with H(e) levels of 9 mumol/L or less (P = .007). For men, the same comparison yielded relative odds of 13.8 (P = .0002). Plasma H(e) remained a strong, independent risk factor after adjustment for standard risk factors and plasma vitamin levels in multiple logistic regression (relative odds, 8.1 for a 10-mumol/L increase in H(e); 95% confidence interval, 3.2 to 20.4; P < .0001). In multivariate ANCOVA the slope of H(e) versus folate was much steeper in subjects with CAD than in control subjects (P = .0035). These data suggest that high plasma H(e) is an important, independent contributor to risk for early familial CAD.(ABSTRACT TRUNCATED AT 250 WORDS)