Pregnancy-associated plasma protein-A (PAPP-A) was studied as a marker of acute coronary syndrome (ACS). It has been shown that its levels are increased by heparin administration. Therefore, the aim of our study was to ascertain the diagnostic significance of PAPP-A in heparin-naïve patients and compare it with (TnI). We prospectively studied 67 heparin-naïve patients with acute chest pain. The patients were independently grouped according to the presence or absence of ACS. PAPP-A levels were significantly increased in ACS patients (8.6 vs. 7.3 mIU/l; P = 0.006) with high positive (95.7%) and lower negative predictive values (47.7%). In multivariate analysis, its levels were strongly predictive of a final diagnosis of ACS (OR 41.8; 95th CI 2.64-662.6; P = 0.008). The diagnostic significance of PAPP-A was not higher than TnI even within 6 h after the onset of chest pain [the area under the ROC curve (AUC) was 0.69 for PAPP-A and 0.91 for TnI, respectively; P = 0.08]. We observed no difference in the AUC in NSTE-ACS patients (0.73 for PAPP-A and 0.79 for TnI (P = 0.5)). PAPP-A levels were an independent predictor of ACS diagnosis in heparin-naïve patients. Its diagnostic significance was not higher than TnI even within a short period after the onset of chest pain. In troponin-negative NSTE-ACS patients, PAPP-A helped make the correct final diagnosis.