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Introduction: Antiphospholipid syndrome (APS) associated with intra-cardiac thrombus and pulmonary embolism is infrequent. However, the presence of pleural effusion is extremely rare. Case Presentation: A 42-year-old woman, admitted with palpitation, dyspnea and history of stroke and thrombocytopenia is described. Doppler sonography revealed deep vein thrombosis. Moreover, subsequent investigation confirmed the presence of right atrial thrombus, pulmonary arteries embolism and bilateral pleural effusion. Inferior vena cava thrombosis was confirmed during cardiac surgery and all thrombi were removed subsequently. Laboratory studies revealed the diagnosis of APS. The patient experienced deep vein thrombosis one year later and no evidence of recurrent disease was documented after three years follow up. Conclusions: APS complicated by inferior vena cava thrombosis coexistence of pulmonary embolism and intra-cardiac thrombus is not previously reported. Moreover, presence of pleural effusion with these conditions describes a unique case of APS.