Background:Pulmonary embolism (PE) is a potentially fatal form of venous thromboembolism (VTE). This study compares the mortality, incidence of recurrent VTE, and incidence of major bleeding between non-cancer and cancer-associated PE patients treated with direct oral anticoagulants (DOACs).Methods and Results:This was a retrospective, observational, single-center study involving 130 consecutive patients (87 with active cancer; 43 without cancer) who received DOAC treatment for PE between January 2016 and December 2019. Kaplan-Meier analysis showed significantly higher mortality in cancer-associated PE patients than in non-cancer patients (35/87 40% vs. 1/43 2%, P<0.001, log-rank test, HR 18.6 95% CI: 2.5–136.0). In contrast, the cumulative incidences of recurrent VTE and major bleeding were comparable between the 2 groups. Among the cancer-associated PE patients, the incidence for the composite outcome of recurrent VTE or major bleeding was significantly higher in patients undergoing chemotherapy than in those not undergoing chemotherapy (9/37 24% vs. 2/50 4%, P=0.004, log-rank test, HR 6.9 95% CI: 1.5–32.0).Conclusions:Although cancer-associated PE patients treated with DOACs showed higher mortality compared with non-cancer patients, presumably because of the presence of cancer, the risk of recurrent VTE or major bleeding was comparable between the 2 groups. Thus, DOAC is an important treatment option for cancer-associated PE, although underlying cancer-related risks (e.g., chemotherapy) remain.