Mean platelet volume (MPV) has been correlated with platelet reactivity, thus its changes might be used to monitor the effects of antiplatelet therapy. However, no data have been reported on platelet remodelling after antiplatelet therapy. The aim of the current study was to investigate the short-term effects of oral antiplatelet therapy on MPV. Our population is represented by 62 consecutive patients with acute coronary syndrome (ACS), who did not receive GpIIb-IIIa inhibitors. We measured MPV before starting dual antiplatelet therapy, at day 1, day 2, and day 3-5 from starting adjunctive antiplatelet therapy. We additionally analyzed the relationship between platelet aggregation and MPV at admission by Multiplate in patients who were on chronic aspirin therapy. We observed a significant paradoxical increase in MPV, with a reduction in platelet count. We observed at all time intervals a significant inverse relationship between MPV and platelet count (T0: r = -0.44, P < 0.0001; T1: r = -0.36, P = 0.006; T2: r = -0.3, P = 0.026; T3-5: r = -0.29, P = 0.046). No relationship was observed between MPV and the extent of platelet aggregation inhibition by aspirin. This study showed a paradoxical increase in MPV after starting antiplatelet therapy. In addition, we did not observe any relationship between baseline MPV and the extent of platelet aggregation inhibition by aspirin. Thus, larger MPV does not imply higher platelet reactivity and may not be considered to monitor platelet reactivity and the efficacy of antiplatelet therapies.