Platelets are small corpuscular elements, which play an essential role in hemostasis and thrombosis. As active players in the thrombotic process, hyperactive platelets are involved in the pathogenesis of cardiovascular disorders. Nevertheless, the role of platelet size, as a biological marker of platelet activation, remains debated in the setting of venous thrombosis. Therefore, we conducted a retrospective case-control study to clarify the potential association between mean platelet volume (MPV) and newly diagnosed venous thromboembolism (VTE) by reviewing data of all consecutive patients receiving a diagnosis of VTE at the emergency department (ED) of the University Hospital of Parma (Italy) between January and December, 2014. The control population was represented by outpatients undergoing routine laboratory testing for health checkup at the phlebotomy center of the same University Hospital during the same period. MPV was found to be comparatively decreased in the entire cohort of patients with VTE compared with the outpatient population, as well as in those with isolated deep vein thrombosis (DVT) or pulmonary embolism (PE). A decreased MPV value (i.e., < 10.8 fL) was found to be associated with an increased risk of diagnosing VTE (relative risk, 1.18; 95% CI, 1.09-1.28; p < 0.001), as well as of diagnosing isolated DVT (relative risk, 1.19; 95% CI, 1.07-1.31; p = 0.001) and isolated PE (relative risk, 1.17; 95% CI, 1.04-1.30; p = 0.007). A decreased MPV value in active cancer patients was associated with the highest risk of diagnosing thrombosis (relative risk, 1.29; 95% CI, 1.10-1.51; p = 0.002). These results support an inverse association between MPV and the risk of venous thrombosis at diagnosis.