Background Optimal dosing of recombinant tissue-type plasminogen activator (rt-PA) is important in treating pulmonary thromboembolism (PTE). Methods Objective The aim of this study was to compare the efficacy and safety of a 50 mg/2 h rt-PA regimen with a 100 mg/2 h rt-PA regimen in patients with acute PTE. Design A prospective, randomized, open label trial. Setting A multicenter trial in China. Subjects 118 patients with acute PTE and either hemodynamic instability or massive pulmonary artery obstruction. Intervention Patients were randomly assigned to receive a treatment regimen of either rt-PA at 50 mg/2 h (n = 65) or 100 mg/2 h (n = 53). Outcomes The efficacy was determined by observing the improvements of right ventricular dysfunctions (RVDs) on echocardiograms, lung perfusion defects on ventilation perfusion lung scans, and pulmonary artery obstructions on CT angiograms. The adverse events, including death, bleeding, and PTE recurrence, was also evaluated. Results Progressive improvements in RVDs, lung perfusion defects, and pulmonary artery obstructions were found to be similar in both treatment groups. This is true for patients with either hemodynamic instability or massive pulmonary artery obstruction. Three (6%) patients in the rt-PA 100 mg/2 h group and one (2%) in the rt-PA 50 mg/2 h group died as the result of either PTE or bleeding. Importantly, the 50 mg/2 h rt-PA regimen resulted in less bleeding tendency than the 100 mg/2 h regimen (3% vs. 10%), especially in patients with a body weight, 65 kg (14.8% vs. 41.2%, P = 0.049). No fatal recurrent PTE was found in either group. Conclusions Compared with the 100 mg/2 h regimen, the 50 mg/2 h rt-PA regimen exhibits similar efficacy and perhaps better safety in patients with acute PTE. These findings support the notion that optimizing rt-PA dosing is worthwhile when treating patients with PTE.