(1) Background: Catheter-directed therapies (CDT) may be considered for selected patients with pulmonary embolism (PE); (2) Methods: Retrospective observational study including all consecutive patients with acute PE undergoing CDT (mechanical or pharmacomechanical) from January 2010 through December 2020. The aim was to evaluate in-hospital and long-term mortality and its predictive factors; (3) Results: We included 63 patients, 43 (68.3%) with high-risk PE. All patients underwent mechanical CDT and, additionally, 27 (43%) underwent catheter-directed thrombolysis. Twelve (19%) patients received failed systemic thrombolysis (ST) prior to CDT, and an inferior vena cava (IVC) filter was inserted in 28 (44.5%) patients. In-hospital PE-related and all-cause mortality rates were 31.7%; 95% CI 20.6–44.7% and 42.9%; 95% CI 30.5–56%, respectively. In multivariate analysis, age > 70 years and previous ST were strongly associated with PE-related and all-cause mortality, while IVC filter insertion during the CDT was associated with lower mortality rates. After a median follow-up of 40 (12–60) months, 11 more patients died (mortality rate of 60.3%; 95% CI 47.2–72.4%). Long-term survival was significantly higher in patients who received an IVC filter; (4) Conclusions: Age > 70 years and failure of previous ST were associated with mortality in acute PE patients treated with CDT. In-hospital and long-term mortality were lower in patients who received IVC filter insertion.