Pregnancy-associated plasma protein-A (PAPP-A) level is an independent predictor of acute cardiovascular event occurrence. To test the hypothesis that increased PAPP-A levels would be associated with a higher burden of coronary thin-cap fibroatheroma (TCFA) thereby underlying the heightened risk for cardiovascular events in patients with coronary artery disease; 154 patients (462 vessels and 975 plaques) with stable angina or non-ST-segment elevation acute coronary syndrome (NSTE-ACS) referred for percutaneous coronary intervention were assessed using 3-vessel virtual histology (VH)-intravascular ultrasound (IVUS). Thin-cap fibroatheroma virtual histology was defined as focal, necrotic core (NC)-rich (>= 10% of cross-sectional area) plaques in contact with the lumen, and plaque burden >= 40%. Pregnancy-associated plasma protein-A levels were determined by sandwich enzyme-linked immunosorbent assay, and patients were divided into 3 groups based on PAPP-A level tertiles. Although the highest PAPP-A level tertile was not associated with 3-vessel plaque number, it was associated with 3-vessel VH-TCFA number and necrotic core volume. Patients with >= 3 VH-TCFAs had a higher PAPP-A level than patients with 1 to 3 VH-TCFAs or without any VH-TCFA (13.3 +/- 11.8 versus 7.8 +/- 4.7 versus 7.4 +/- 4.7 mIU/L, P < 0.001, respectively). Moreover, PAPP-A level was an independent predictor of higher total number of VH-TCFAs (OR 1.18; 95% CI 1.07-1.29, P = 0.001). This VH-IVUS study demonstrated, for the first time to our knowledge, that higher PAPP-A levels are associated with higher 3-vessel TCFA burden in patients with coronary artery disease. Pregnancy-associated plasma protein-A, therefore, might be a useful serum biomarker to predict increased coronary TCFA burden and plaque instability.