The Anti-phospholipid syndrome (APS) whether primary or associated with auto-immune disorders can be accompanied by many thrombotic events. Possible mechanisms include the effects of inflammatory activity and antiphospholipid antibodies (aPLs). The only available oral anticoagulant drugs have been vitamin K antagonists (VKA). New oral anti-coagulants have proved their effectiveness in other situations. It is the aim of this review to explore a possible role for the new Oral Direct Inhibitors (ODI) in the management of (APS)-associated thrombosis highlighting the possible obstacles of their use in that context. Primary Anti-phospholipid syndrome is characterized by thrombosis and/or pregnancy morbidity occurring in patients with persistent aPLs. It comprises a broad spectrum: a) asymptomatic aPL positivity (no history of thrombosis or pregnancy morbidity); b), livedo reticularis, thrombocytopenia, hemolytic anemia, cardiac valve disease, aPL-associated nephropathy, skin ulcers, or cognitive dysfunction; c) pregnancy morbidity (recurrent embryonic or fetal loss, preeclampsia, and growth restriction); d) venous, arterial, or small vessel thrombosis; and e) catastrophic Anti-phospholipid syndrome (CAPS) (multiple organ thromboses commonly associated with microangiopathy.