Objectives. We sought to assess the technical and clinical feasibility of continuous aspiration catheter-directed mechanical thrombectomy (CDT) in patients with high- or intermediate-high-risk pulmonary embolism (PE). Methods and Results. Fourteen patients (eight women and six men; age range: 29–71 years) with high- or intermediate-high-risk PE and contraindications to or ineffective systemic thrombolysis were prospectively enrolled between October 2018 and February 2020. The Indigo Mechanical Thrombectomy System (Penumbra, Inc., Alameda, California) was used as CDT device. Low-dose local thrombolysis (alteplase, 3–12 mg) was additionally applied in three patients. Technical and procedural success was achieved in 14 patients (100%). Complete or nearly complete clearance of pulmonary arteries was achieved in nine patients (64.3%), whereas partial clearance was achieved in five (35.7%). A significant improvement in the pre- and postprocedural patients’ clinical status was observed in the following fields (median; interquartile range): heart rate (110; 100–120/min vs. 85; 80–90/min; p < 0.0001 ), systolic blood pressure (106; 90–127 mmHg vs. 123; 110–133 mmHg; p = 0.049 ), arterial oxygen saturation (88.5; 84.2–93% vs. 95.0; 93.8–95%, p = 0.0051 ), pulmonary artery systolic pressure (55; 44–66 mmHg vs. 42; 34–53 mmHg; p = 0.0015 ), Miller index score (21.5; 20–23 vs. 9.5; 8–13; p < 0.0001 ) and right ventricular/left ventricular ratio (1.3; 1.3–1.5 vs. 1.0; 0.9–1.0; p < 0.0001 ). No major periprocedural bleeding was detected. Conclusions. CDT is a feasible and promising technique for management of high- or intermediate-high-risk PE to decrease thrombus burden, reduce right heart strain, and improve hemodynamic and clinical status. Some patients may benefit from simultaneous local low-dose thrombolytic therapy. Nevertheless, its criteria and role in CTD-managed patients require further elucidation.