Mean platelet volume (MPV) is a marker of platelet activation. An increased MPV is associated with acute myocardial infarction (AMI) and long-term mortality. The aim of this study was to compare MPV in patients with ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI). Also, we investigated the value of MPV on in-hospital mortality and long-term prognosis of patients with STEMI and NSTEMI. We studied 429 patients with AMI (70.4% male, 61.9 ± 12.4 years; 279 patients with STEMI, 150 patients with NSTEMI). MPV and platelet count were similar in both groups. Elevated MPV increased the risk of death by 3.1-fold (p < 0.001) in STEMI group during the hospitalization. However, increased MPV was not associated with in-hospital mortality in NSTEMI group. The area under the receiver operating characteristic curve of MPV was 0.868 (95% CI, 0.830-0.907) for predicting two-year mortality. A cut-off point of 11.1 fL showed a sensitivity of 81% and a specifity of 77% for prediction of two-year mortality. Kaplan-Meier survival curve showed two-year mortality rate of 12.5% in patients with MPV >11.1 fL versus 9.9% in patients with MPV <11.1 fL (p < 0.001). Cox regression analysis showed MPV to be an independent predictor of two-year mortality (Hazard ratio 1.7; 95% CI 1.5-1.9; p < 0.001). An increased MPV is an independent predictor of in-hospital mortality in patients with STEMI. However, elevated levels of MPV did not predict in hospital mortality in NSTEMI group. The increase in MPV values was independently correlated with two-year mortality in all study patients.