No data are available on the efficacy and safety of a combination of fondaparinux and thrombolysis in the setting of high to intermediate risk pulmonary embolism (PE). Patients submitted to thrombolysis and fondaparinux, presenting with ≥1 of the following criteria were included: (1) cardiogenic shock, (2) syncope, (3) ≥1 proximal thrombo-embolus at CT scan, (4) positive troponin test, (5) echocardiographic findings indicating right ventricular (RV) dysfunction. In-hospital results included death, recurrent PE, persistent RV dysfunction at 48 h echocardiography, bleeding complications. Twenty seven patients were included; 22 received a 2 h infusion of rt-PA and 5 received a 2 h infusion of streptokinase. Ten patients presented with cardiogenic shock (37%), 8 with syncope (30%), all had RV dysfunction. 82% of patients had an uneventful in-hospital course. One patient died during hospital stay from refractory shock. Thrombolysis failed in 2 patients (7%), requiring successful rescue surgical embolectomy. Bleeding events occurred in 2 patients (7%), of whom 1 required blood transfusion. Despite the small sample size, our data suggest that fondaparinux procures adequate tolerability compared to standard current therapy in combination with thrombolysis in high to intermediate risk PE.