OBJECTIVE: In patients with uncomplicated diabetes, there is low probability of finding significant coronary artery disease (CAD) by noninvasive tests. Therefore, screening for its presence is not justified, and it is important to find reliable predictors of silent CAD to identify patients with uncomplicated diabetes for further screening. The relationship between lipoprotein(a) [Lp(a)], apolipoprotein(a) [apo(a)] polymorphism, and silent CAD has never been studied. We investigated the association of Lp(a) and apo(a) polymorphism with angiographically documented asymptomatic CAD in type 2 diabetic patients without evident complications. RESEARCH DESIGN AND METHODS: A total of 1,323 diabetic patients without any clinical and electrocardiographic evidence of CAD were evaluated. Of 121 patients with highly positive results of exercise electrocardiography (ECG) (n = 30) or positive results on exercise thallium scintigraphy (n = 91), 103 subjects showed angiographically documented CAD (CAD group). Of 1,106 patients with negative results on exercise ECG, 103 subjects without CAD (NO CAD group) were selected and matched by age, gender, and duration of diabetes to patients in the CAD group. In patients in the NO CAD group, results of exercise ECG, 48-h ambulatory ECG, and stress echocardiography were negative for CAD. RESULTS: The CAD group had higher Lp(a) levels (21.7 +/- 17.7 vs. 15.2 +/- 19.0 mg/dl; P = 0.0093) than the NO CAD group, and a percentage of subjects had at least one small apo(a) isoform (68.9 vs. 29.1%; P = 0.0000) higher than the NO CAD group. Logistic regression analysis showed that apo(a) phenotypes (odds ratio [OR] 8.13, 95% CI 3.65-21.23), microalbuminuria (5.38, 2.44-11.88), smoking (2.72, 1.31-5.64), and Lp(a) levels (2.41, 1.15-5.03) were predictors of asymptomatic CAD. CONCLUSIONS: Our investigation reports the first evidence of an independent association of Lp(a) and apo(a) polymorphism with asymptomatic CAD. This suggests that Lp(a) levels and apo(a) phenotypes could be used together with other risk factors as markers of asymptomatic CAD in patients with diabetes.