Objective: Acute coronary syndrome (ACS) is a challenging issue in cardiovascular medicine. Given platelet role in atherothrombosis, we sought to determine whether platelet indices can be used as diagnostic tests for patients who suffered from an acute chest discomfort. Methods: We prospectively enrolled 862 patients with an acute chest pain and 184 healthy matched controls. They were divided into four groups: 184 controls, 249 of non-ACS, 421 of unstable angina (UA), and 192 of myocardial infarction (MI) cases. Blood samples were collected at admission to the emergency department for routine hematologic tests. Results: The mean platelet volume (MPV), platelet distribution width (PDW), and platelet large cell ratio (P-LCR) were significantly greater in patients with MI compared with those of non-ACS or control subjects. Negative and significant correlations existed between MPV, PDW, and P-LCR values and platelet count (P < 0.001). Receiver operating characteristic (ROC) curves showed that the MPV, PDW, and P-LCR with cut-off values of 9.15 fL, 11.35 fL, and 20.25% and with area under the curves of 0.563, 0.557, and 0.560, respectively, detected MI patients among those who had chest discomfort. The sensitivities and specificities were found to be 72% and 40%, 73% and 37%, and 68% and 44% for MPV, PDW, and P-LCR, respectively. Conclusion: An elevated admission MPV, PDW, and P-LCR may be of benefit to detect chest pain resulting in MI from that of non-cardiac one, and also for risk stratification of patients who suffered from an acute chest discomfort.