Superior vena cava syndrome (SVCS), is diagnosed following different degrees of central venous system obstruction, which traditionally was caused by infections, tumors or fibrosing mediastinitis. Recently the role of SVC thrombosis secondary to indwelling central venous devices or pacemaker leads as well as different hypercoagulable states have drawn much attention. In the current review we present a 58-year-old female patient who underwent recurrent pacemaker replacements due to recurrent infections. The patient was hospitalized with superior vena cava syndrome and multiple thrombi in the upper body circulation. Additionally the evaluation was conducted for thrombophilia, which revealed the presence of high titers of antiphospholipid antibodies, suggesting the concurrent diagnosis of the antiphospholipid syndrome (APS). This case reflects the changes in the etiology of SVCS, and the need for a comprehensive evaluation of patients, in the search for additional factors that may complicate a pacemaker insertion, such as the presence of antiphospholipid antibodies. We review the relevant literature and highlight the importance for an interdisciplinary approach in the treatment of SVCS nowadays.