Background The objective was to compare immediate and long-term results of systemic thrombolytic therapy (STT) and catheter-directed fragmentation (CDF) with local thrombolytic therapy (LTT) in patients with massive pulmonary embolism (PE). Methods About 209 patients with massive PE (the high risk of early death) were included in our study. From 2008 till 2010 in the first group (n = 102), STT was performed. From 2011 till 2013 in the second group (n = 107), CDF with LTT was carried out. Echocardiography and pulmonary arteriography were performed in all patients on admission to hospital and in 5 days after treatment. The patients of both groups were re-examined in 6 months, 1, 2, and 3 years after the operation. Results In the first group, there were 5 (4.9%) cases of in-hospital 30-day mortality. In the second group, there was 1 (0.9%) case of in-hospital 30-day mortality (P = 0.08). In the first group, a clinically significant bleeding was noted in 4 (3.9%) cases, but it caused mortality only in 1 case. In the second group, the clinically significant bleeding was not found (P = 0.038). Persistent postembolic pulmonary hypertension (PPPH) in 9.8% cases of patients in the first group and 2.9% cases of patients in the second group was determined (P = 0.048). Conclusions CDF combined with LTT is an effective minimal invasive treatment (helped us to reduce significantly the number of bleeding and PPPH cases), at least in the midterm, in patients with massive PE.