Study Objectives: We tested the hypothesis that implementation of a protocol combining risk-stratification, treatment with the direct acting oral anticoagulant rivaroxaban, and defined follow-up would increase the number of PE patients discharged directly from the emergency department (ED) or ED observation unit (EDOU) after pulmonary embolism (PE) diagnosis, but would not be associated with increased mortality, major bleeding or hospital readmission among those discharged. Methods: We performed a multicenter study (NCT02532387) of patients diagnosed with PE or DVT in the EDs of two large, urban teaching hospitals, for 16 months before and after implementing our outpatient PE treatment protocol in October 2015. Physicians were educated about the protocol, but decisions regarding outpatient treatment were at physician discretion. Subjects were identified using a combination of screening in the ED and review of medical records. PE and DVT were objectively confirmed by imaging. Outpatient treatment was defined as discharge from the ED or EDOU. We used Fisher's Exact tests to compare proportions of patients with PE and DVT discharged before and after protocol implementation. We used the total number of patients diagnosed with DVT or PE as the denominators for our analyses. We performed pre-planned subgroup analyses according to: hospital, DVT and PE, and patients discharged directly from the ED (ie, not EDOU). We performed safety analyses analyzing the proportion of deaths, major bleeding events, and hospital readmission in the subgroup of discharged patients. Results: We enrolled 2318 patients with PE or DVT; 1073 (46%) before and 1245 (54%) after protocol implementation. Mean age (59AE17 vs. 60AE17), the proportions of female (49% vs. 49%), white race (76% vs. 81%) and PE diagnosis (59% vs. 56%) were similar before and after. The proportion of PE patients discharged from the ED or EDOU increased after protocol implementation (66 [10.5%] vs. 104 [14.8%], p¼0.02). At one hospital, the increase was more pronounced (40 [12.2%] vs. 70 [19.9%], p¼0.007). The proportion of DVT patients discharged from the ED or EDOU did not change (223 [50.5%] vs. 283 [50.4%], p¼0.54), but more DVT (136 [30.8%] vs. 200 [37.0%], p¼0.04) and PE (34 [5.4%] vs. 57 [8.1%], p¼0.05) were discharged directly from the ED after protocol implementation. Most patients (n¼201 [58.9%]) were discharged on rivaroxaban after protocol implementation; a significant increase vs. before protocol implementation (n¼32 [24.2%]), p<0.001. There was no change in 7-day mortality (0 [0%] vs. 1 [0.3%], p¼1.00), major bleeding (0 [0%] vs. 1 [0.26%], p¼1.00), or hospital readmissions (26 [9.0%] vs. 24 [6.2%], p¼0.17) among discharged patients before and after protocol implementation. Conclusions: Real-world implementation of an outpatient treatment protocol, combining risk stratification and rivaroxaban treatment, increases the proportion of PE patients who can safely be discharged from the ED.