Multiple studies have demonstrated that elevated serum lipoprotein (a) [Lp(a)] levels are independent predictors for coronary artery disease (CAD) in subjects without diabetes mellitus (DM). However, their contribution in patients with DM is controversial and still requires clarification. We determined serum Lp(a) levels in 355 consecutive Caucasian patients (271 men and 84 women) with angiographically documented CAD, and in 100 control subjects (58 men and 42 women) who were clinically free of cardiovascular disease. In addition, the association of serum Lp(a) levels with type-2 DM in patients with CAD was investigated after reassigning patients according to the diagnosis of type-2 DM (61 men and 40 women with type-2 DM and 210 men and 44 women without). No gender differences in Lp(a) levels were observed between men and women (patients and control subjects). Patients with CAD had higher Lp(a) levels than the control subjects (33 (14-74) vs. 13 (9-29) mg/dl, P<0.001). Elevated Lp(a) levels (defined as >90th percentile of controls) were significantly more prevalent in men and women with CAD (35% and 28%, respectively) than in control subjects (13% and 10%, respectively). Serum Lp(a) levels correlated with LDL cholesterol (r=0.22, P<0.001) and apo B levels (r=0.18, P<0.03) in patients and control subjects. Stepwise discriminant analysis revealed that Lp(a) was an independent risk factor for the presence of CAD, independent of smoking, hypertension, type-2 DM, LDL and HDL cholesterol or apo A1 and B levels. When patients were studied according to the spread of CAD (evaluated as the number of narrowed vessels), no differences in serum Lp(a) levels were observed, nor was there a higher prevalence of elevated Lp(a) levels. Finally, when patients were re-assigned according to the diagnosis of type-2 DM, no effect of apo B and LDL-C levels on Lp(a) was found (r=0.06, P=n.s. and 40.14, P=n.s., respectively) and serum Lp(a) levels neither associated nor contributed to the extent of CAD. Our results showed that serum Lp(a) levels are increased in patients with angiographically documented CAD, but there were no significant differences between diabetic and non-diabetic patients, which indicates that elevated Lp(a) levels are specifically associated with CAD but not with type-2 DM.