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Summary: Anti‐phospholipid syndrome (APS) is characterized by arterial and/or venous thrombosis and pregnancy morbidity. It is well known that in these patients thrombosis may be the result of a hypercoagulable state related to anti‐β2‐glycoprotein I (β2‐GPI) antibodies. Moreover, platelets may play a role in thrombotic manifestations by binding of anti‐β2‐GPI antibodies. Platelets express tissue factor (TF), the major initiator of the clotting cascade, after activation. We primarily analyzed whether anti‐β2‐GPI antibodies may trigger a signal transduction pathway leading to TF expression in human platelets. Platelets from healthy donors were incubated with affinity purified anti‐β2‐GPI antibodies for different times. Platelet lysates were analyzed for phospho‐interleukin‐1 receptor‐associated kinase 1 (IRAK), phospho‐p65 nuclear factor kappaB (NF‐κB) and TF by Western blot. IRAK phosphorylation was observed as early as 10 min of anti‐β2‐GPI treatment, with consequent NF‐κB activation, whereas TF expression, detectable at 45 min, was significantly increased after 4 h of anti‐β2‐GPI treatment. Virtually no activation was observed following treatment with control immunoglobulin IgG. We then analyzed TF expression in platelets from 20 APS patients and 20 healthy donors. We observed a significant increase of TF in APS patients versus control subjects (P < 0·0001). This work demonstrates that anti‐β2‐GPI antibodies may trigger in vitro a signal transduction pathway in human platelets, which involves IRAK phosphorylation and NF‐κB activation, followed by TF expression. Furthermore, ex vivo, platelets of APS patients showed a significantly increased expression of TF. These findings support the view that platelets may play a role in the pathogenesis of APS, with consequent release of different procoagulant mediators, including TF. Anti‐β2‐GPI antibodies may trigger in vitro a signal transduction pathway in human platelets, which involves IRAK phosphorylation and NF‐κB activation, followed by TF expression. Furthermore, platelets of APS patients showed a significantly increased expression of TF. These findings support the view that platelets play an important role in the pathogenesis of APS. [ABSTRACT FROM AUTHOR]