Porphyromonas gingivalis (PG) plays a key role in periodontitis. From dental plaque, bacteria also enter the blood stream and contribute to the pathophysiology of cardiovascular diseases. PG directly activates human platelets by a variety of mechanisms involving outer membrane structures and stimulation of protease-activated receptors by gingipains. Here, we investigate molecular mechanisms of platelet activation by various PG isolates. Methods: PG isolates from 12 patients with acute periodontitis were investigated for their ability to activate human platelets by light transmission aggregometry and expression of the platelet surface marker P-selektin. Intracellular signalling pathways involved in platelet activation were determined by Western blot technique. In 4 patients with recurrent colonization after antibiotic therapy, PG isolates before and after therapy were compared. Results: PG isolates showed high variability in platelet activation ranging from 0 to 100% aggregation. Furthermore, the time period for onset of aggregation varied between 1 and 9 minutes indicating that PG isolates use different platelet activation mechanisms. Corresponding results were obtained for platelet P-selektin expression and activation of intracellular activatory platelet pathways (e.g. MAP kinases or protein kinase C): while the majority of isolates activated platelet immune receptor FcγIIR and protease-activated receptors, 4 isolates used alternative pathways. Furthermore, 3 isolates induced platelet aggregation despite the presence of potent platelet inhibitors such as acetyl salicylic acid or nitrates. PG isolates from patients with recurrent colonization showed similar characteristics before and after therapy suggesting clonal persistence or reinfection during the study. Conclusions: Interaction of platelets with individual PG isolates underlies high variability with regard to the degree of platelet activation and platelet signalling pathways activated. Certain PG isolates even induce platelet activation despite the presence of strong therapeutic platelet inhibitors. This variability of PG isolates may have an important pathogenetic impact on aggravation of cardiovascular diseases in patients with periodontal disease. Keywords: Platelet activation, Prophyromonas gingivalis, molecular mechanisms, Periodontitis