The role of platelets in hemostasis and thrombosis has long been recognized, recently their contribution to immunological and inflammatory processes is emerging. Platelets could be the missing link between cardiovascular disease, chronic stress and depressive symptoms. Both physical and mental stressors cause platelet activation reflected by changes in platelet bioactivity and aggregation. Here we evaluate the proinflammatory platelet response to acute and chronic mental stress. In a prospective study design an acute mental stress test was administered to 55 healthy male participants once without and once in the presence of chronic mental stress. Blood was collected prior to and at three time points following an acute mental stress test (0, 30, 60 min). Platelet proinflammatory activation markers, were assessed using FACS analysis and aggregability was measured in response to ADP or epinephrine using PFA-100. A linear mixed model was used for analysis. Chronic mental stress lead to a significant increase in state anxiety ( p  < 0.001), depressive symptoms ( p  = 0.045) and perceived stress ( p  = 0.001). The factor “chronic mental stress” was significantly associated with increased numbers of CD63+ platelets ( p  = 0.009). The factor “acute mental stress” was associated with alterations in CD62P+ platelets ( p  < 0.001), CD63+ platelets ( p  = 0.011), PAC-1+ platelets (p < 0.001) as well as platelet leucocyte aggregates ( p  = 0.019). The recovery of CD62P function following the acute mental stress exposure was significantly impaired by chronic stress ( p  = 0.023). Aggregation was affected by chronic and acute mental stress. In conclusion, mental stress is linked to an increased and prolonged proinflammatory platelet bioactivity. This proinflammatory and immunomodulatory stimuli could help to explain the link between mental and somatic disorders. Graphical Abstract