We performed this investigation to determine the effects on mortality of thrombolytic therapy in low-risk patients with pulmonary embolism (PE). This was a retrospective cohort study based on administrative data from the Nationwide Inpatient Sample, 2016 and 2017. Patients with a primary (first-listed) diagnosis of acute PE who were not in shock and not on a ventilator who did not have acute cor pulmonale were defined as low-risk. Patients were identified by International Classification of Diseases-10-Clinical Modification Codes. Mortality was assessed according to treatment with catheter-directed thrombolysis, intravenous thrombolytic therapy, or anticoagulants alone. Mortality with inferior vena cava (IVC) filters was also assessed. Mortality was lowest in low-risk patients treated with anticoagulants alone, 6,765 of 331,430 (2.0%). Mortality was somewhat higher with catheter-directed thrombolysis, 195 of 6915 (2.8%)(p<0.0001), and highest with intravenous thrombolysis 510 of 5,200 (9.8%)(p<0.0001). Matched patients showed similar results. Inferior vena cava filters did not reduce mortality in patients treated with anticoagulants alone. Mortality was only 0.5% higher in patients treated with anticoagulants who had saddle PE than in patients with non-saddle PE, 450 of 17,935 (2.5%) vs 6,315 of 313,495 (2.0%)(p<0.0001). However, a larger proportion of low-risk patients with saddle PE received catheter-directed thrombolysis than patients who had non-saddle PE, 2,330 of 21,760 (11%) vs 4,585 of 321,785 (1.4%)(p<0.0001). Similarly, a larger proportion of patients with saddle PE received intravenous thrombolytic therapy than patients with non-saddle PE, 1,495 of 21,760 (6.9%) vs 3,705 of 321,785 (1.2%)(p<0.0001). In conclusion, low-risk patients with PE did not have lower mortality with catheter-directed thrombolysis or intravenous thrombolytic therapy than with anticoagulants alone, and IVC filters did not reduce mortality with anticoagulants alone.