Purpose: To evaluate if sedation with propofol during catheter-directed thrombolysis (CDT) in patients with acute submassive pulmonary embolism (PE) affects survival., Materials and Methods: This single-institution, retrospective study identified 136 patients from 2011-2017 who underwent CDT for acute submassive PE. Patients were grouped based on procedural sedation-propofol versus fentanyl and/or midazolam. Groups were compared for differences in baseline characteristics. Primary endpoint was in-hospital mortality. Logistic regression analysis was performed to evaluate for independent variables predictive of mortality. Propensity-matched analysis was also performed., Results: Propofol was given to 18% (n = 25) of patients, and fentanyl and/or midazolam was given to 82% (n = 111) of patients. Mortality was 28% (n = 7) in the propofol group versus 3% (n = 3) in the fentanyl/midazolam group (P = .0003). Patients receiving propofol had 10.4 times the risk of cardiopulmonary arrest or dying during hospitalization compared with patients receiving fentanyl and/or midazolam (95% confidence interval, 2.9-37.3, P = .0003). The number needed to harm was 4 (95% confidence interval, 2.8-6.8). Logistic regression model analysis including Pulmonary Embolism Severity Index score, right-to-left ventricle diameter ratio and age was not predictive of mortality (P = .19). Adding type of sedation made the model predictive of mortality (P < .001). Propensity-matched analysis controlling for baseline differences in age, adjunctive maneuvers, American Society of Anesthesiologists class, and intubation before the procedure revealed that statistical significance between groups remained (P = .01)., Conclusions: Sedation with propofol during CDT for acute submassive PE is associated with increased mortality and should be used with caution., (Copyright © 2019 SIR. Published by Elsevier Inc. All rights reserved.)