Purpose To evaluate effectiveness and safety of large-bore mechanical thrombectomy of intermediate- or high-risk pulmonary embolism (PE) and factors associated with effectiveness. Materials and Methods A retrospective review of 257 patients with intermediate- or high-risk PE who underwent mechanical thrombectomy using the Flowtriever system (Inari Medical, Irvine, California) between July 2019 and November 2021 was conducted. Data were analyzed using the linear regression and Kaplan-Meier methods with a Type 1 error set at 0.05. Results Patients' mean age was 62 years, and 51% were male. PE risk was classified as high, intermediate-high, and intermediate-low in 37 (14%), 201 (78%), and 18 (7%) of the patients, respectively. Procedural technical success was 100%. The mean pulmonary artery pressure (MPAP) decreased from a mean of 32 mmHg (SD ± 9) before to 24 mmHg (SD ± 9) after thrombectomy (mean decrease, 8 mmHg [SD ± 6]; P < .0001). Immediate complications occurred in 2% of the patients. Postprocedural 30-day and all-time PE-attributable mortality in a mean of 1.3-year follow-up was 2% and 6%, respectively. In multivariate analysis, the presence of lower extremity DVT at presentation (β ± SE, −7.60 ± 3.22; P = .019) and a higher prethrombectomy MPAP (β ± SE, −0.19 ± 0.04; P < .001) were associated with lower degrees of decrease in MPAP in the intermediate-high–risk PE group. Among 14 patients with postthrombectomy PE-attributable mortality, 13 had postthrombectomy MPAPs of >20 mmHg. Conclusions Large-bore aspiration thrombectomy is a safe and effective treatment for reducing PAP in patients with intermediate- or high-risk PE. Postthrombectomy MPAPs of >20 mmHg might indicate postthrombectomy PE-attributable mortality in high-risk patients.