Background Suspected cardiac chest pain accounts for over 25% of medical admissions but, as only a minority have acute coronary syndromes, there is a tremendous potential to reduce unnecessary admissions. We evaluated five markers of plaque rupture or instability as indicators that would allow safe early exclusion of acute myocardial infarction (AMI) at the time of presentation. Methods Blood was drawn at the time of presentation from patients presenting to the Emergency Department with suspected cardiac chest pain and tested for cTnT and 5 novel biomarkers (pregnancy-associated plasma protein A (PAPP-A), thrombospondin, CD40 ligand, E-selectin and P-selectin). The primary outcome was a diagnosis of AMI. The secondary outcome was the occurrence of death, AMI or urgent revascularization (adverse cardiac events, ACE) within 30 days. Results 713 patients were included. Median time from symptom onset to venepuncture was 210 min. Only P-selectin and PAPP-A had value for diagnosis of AMI, with C-statistics of 0.68 (95% CI 0.63–0.73) and 0.57 (0.51–0.63) respectively. On multivariate analysis, P-selectin, cTnT and ECG ischemia independently predicted ACE. A model combining all three had 97.6% sensitivity, 52.8% specificity and 99.0% negative predictive value (NPV) for AMI. Use of this model could obviate the need for hospital admission in 44.2% of patients, 2.5% of whom would be expected to develop ACE. Conclusions P-selectin has early diagnostic value for AMI and prognostic value independent of cTnT and ECG findings. The combination of P-selectin, cTnT and ECG has high NPV. Further research into this promising biomarker is warranted.