We planned a prospective study to assess platelet number and size in patients with or without brain injury after mild head trauma (MHT). Platelet count and mean platelet volume (MPV) were assessed in consecutive patients admitted to the emergency department with isolate MHT, as well as in healthy blood donors who served as controls. The study population consisted in 54 patients with MHT, 13 of whom (24%) with intracranial lesions suggestive for brain injury, and 339 healthy blood donors. The value of platelet count was significantly lower in patients with MHT and positive computerized tomography than in healthy controls (P = 0.014). The vales of MPV progressively decreased from healthy controls (11.1 fl) to patients with MHT and negative computerized tomography (9.8 fl; P < 0.001), and further to patients with MHT and positive computerized tomography (8.6 fl; P < 0.001). The MPV was significantly lower in patients with MHT and positive computerized tomography than in those with negative computerized tomography (P = 0.002). As compared with healthy controls, the frequency of decreased MPV values was 10-fold and 17-fold higher in MTH patients with negative and positive computerized tomography, respectively. The MPV exhibited an area under the curve of 0.74 (95% CI, 0.58 to 0.89; P < 0.001) for differentiating MHT patients with positive computerized tomography from those with negative computerized tomography. MHT patients display a larger prevalence of small and hyporeactive platelets. This observation provides a reliable basis for planning further studies to establish whether MPV may be useful for diagnostic evaluation of MHT in the emergency department.