Abstract Background/Introduction There is still uncertainty about the optimal usage of thrombolysis for acute pulmonary embolisms (PEs), leading to widely varying usage of thrombolysis in the real world. However, these have not been fully evaluated yet. Purpose We sought to evaluate the management strategies and clinical outcomes of thrombolysis for acute PEs in the real world. Methods The COMMAND VTE Registry is a multicenter registry enrolling 3,027 consecutive patients with acute symptomatic venous thromboembolisms in Japan between January 2010 and August 2014. The present study population consisted of 1,549 patients with PEs who received tissue plasminogen activator (t-PA) thrombolysis (N=180, 12%), or those who did not (N=1,369). The effectiveness outcome was all-cause death. The safety outcome was major bleeding. We used a multivariable logistic regression analysis to estimate the odds ratio (OR) and 95% confidence intervals (CI), to adjust clinically relevant confounders (age, sex, history of major bleeding, active cancer, and anemia). Additionally, we conducted stratified analysis by clinical severity, and we also evaluated clinical outcomes according to dosages of t-PA. Results Patients with t-PA thrombolysis were younger, and more frequently had higher body weight, but less frequently had active cancer, history of major bleeding, and anemia. More than half of patients with t-PA thrombolysis were patients with mild PEs, and the proportions of t-PA thrombolysis varied widely across the participating centers. More than half of patients received low-dose of t-PA (<20,000 IU/kg). As for the effectiveness, 9 (5.0%) patients in the t-PA thrombolysis group and 95 (6.9%) patients in the non t-PA thrombolysis group died at 30 days (Crude OR, 0.71; 95% CI 0.35–1.42, P=0.33). As for the safety, 7 (3.9%) patients in the t-PA thrombolysis group and 22 (1.6%) patients in the non t-PA thrombolysis group experienced major bleeding events at 10 days (Crude OR, 2.48; 95% CI 1.04–5.88, P=0.04). T-PA thrombolysis group had a significantly higher risk for 10-day major bleeding (Adjusted OR, 4.01; 95% CI 1.57–10.2, P=0.004), but not a lower risk for 30-day mortality (Adjusted OR, 1.10; 95% CI 0.53–2.28, P=0.79), although the risk for 30-day mortality was significantly lower in those with severe PEs (Adjusted OR, 0.36; 95% CI 0.15–0.88, P=0.02). After adjusting confounders, the 10-day major bleeding risk of the low-dose of t-PA group relative to the standard-dose of t-PA group tended to be lower (Adjusted OR, 0.07; 95% CI 0.004–1.05, P=0.05). Conclusions In the present real-world registry, relatively large number of patients received t-PA thrombolysis with wide variation across the participating centers. T-PA thrombolysis was significantly associated with a higher risk for major bleeding, but not a lower risk for mortality, although there appeared to be a benefit of t-PA thrombolysis in decreasing the risk for mortality in patients with severe PEs. Acknowledgement/Funding Research Institute for Production Development, Mitsubishi Tanabe Pharma Corporation