Background: In patients with a high clinical probability of pulmonary embolism (PE), the high prevalence can lower the D-dimer negative predictive value and increase the risk of diagnostic failure. It is therefore recommended that these high-risk patients should undergo chest imaging without D-dimer testing although no evidence supports this recommendation. Objective: The objective was to evaluate the safety of ruling out PE based on D-dimer testing among patients with a high clinical probability of PE. Methods: This was a post hoc analysis of three European studies (PROPER, MODIGLIANI, and TRYSPEED). Patients were included if they presented a high clinical probability of PE (according to either the Wells or the revised Geneva score) and underwent D-dimer testing. The D-dimer–based strategy ruled out PE if the D-dimer level was below the age-adjusted threshold (i.e., <500 ng/mL in patients aged less than 50 and age × 10 ng/mL in patients older than 50). The primary endpoint was a thromboembolic event in patients with negative D-dimer either at index visit or at 3-month follow-up. A Bayesian approach estimated the probability that the failure rate of the D-dimer–based strategy was below 2% given observed data. Results: Among the 12,300 patients included in the PROPER, MODIGLIANI, and TRYSPEED studies, 651 patients (median age 68 years, 60% female) had D-dimer testing and a high clinical probability of PE and were included in the study. PE prevalence was 31.3%. Seventy patients had D-dimer levels under the age-adjusted threshold, and none of them had a PE after follow-up (failure rate 0.0% [95% CI 0.0%–6.5%]). Bayesian analysis reported a credible interval of 0.0%–4.1%, with a 76.2% posterior probability of a failure rate below 2%. Conclusions: In this study, ruling out PE in high-risk patients based on D-dimer below the age-adjusted threshold was safe, with no missed PE. However, the large CI of the primary endpoint precludes a definitive conclusion. © 2024 The Author(s). Academic Emergency Medicine published by Wiley Periodicals LLC on behalf of Society for Academic Emergency Medicine.< Réduire