BACKGROUND: Data on thrombolytic therapy disclose benefits from thrombolytic therapy in patients with massive and submassive pulmonary embolism (PE). Previously published case reports have described the successful use of tenecteplase under these conditions. METHODS: Four patients with massive and submassive PE received a weight-optimized dosing regimen of tenecteplase, administered as an intravenous bolus. RESULTS: All patients experienced clinically relevant improvement of dyspnea following thrombus regression. Regression of right ventricular enlargement was documented in three cases. Tenecteplase was well tolerated and did not cause bleeding complications. Thirty-day mortality was zero. CONCLUSIONS: These data support the use of this new thrombolytic agent in patients with massive and submassive PE; however, sufficiently powered, randomized trials have not yet taken place for these indications.