Splenic infarction is a rare feature of infectious mononucleosis (IM) due to Epstein-Barr virus (EBV), limited to three case reports. We report the first case of splenic infarction during acute EBV infection associated with the transient induction of antiphospholipid antibodies. We discuss the role of antiphospholipid antibodies in thrombosis in acute viral infections and postulate other mechanisms of thrombosis. Once other more common causes of splenic infarction, such as endocarditis and lymphoma, have been excluded, the possibility of viral-induced antiphospholipid antibodies should be considered.