Background: The aim of this trial-based economic evaluation was to assess the incremental costs and cost-effectiveness of the modified diagnostic strategy combining the YEARS rule and age-adjusted D-dimer threshold compared with the control (which used the age-adjusted D-dimer threshold only) for the diagnosis of pulmonary embolism (PE) in the Emergency Department (ED). Methods: Economic evaluation from a healthcare system perspective alongside a non-inferiority, crossover, and cluster-randomized trial conducted in 16 EDs in France and two in Spain with three months of follow-up. The primary endpoint was the additional cost of a patient without failure of the diagnostic strategy, defined as venous thromboembolism (VTE) diagnosis at 3months after exclusion of PE during the initial ED visit. Mean differences in 3-month failure and costs were estimated using mixed linear regression models, adjusted for strategy type, period, and the interaction between strategy and period as fixed effects and the hospital as a random effect. The incremental cost-effectiveness ratio (ICER) was obtained by dividing the incremental costs by the incremental frequency of VTE. Results: Of the 1414 included patients, 1217 (86%) were analyzed in the per-protocol analysis (648 in the intervention group and 623 in the control group). At three month, there were no statistically significant differences in total costs (€-47; 95% CI: €-103 to €4), and the failure rate was non inferior in the intervention group (-0.64%, one-sided 97.5% CI: -∞ to 0.21%, non-inferiority margin 1.5%) between groups. The point estimate of the incremental cost-effectiveness ratio (ICER) calculated that each patient without diagnostic failure was associated with cost savings of €7,343 in the intervention strategy compared with the controls. There was a 90% probability that the intervention was dominant. Similar results were found in the as randomized population. Conclusions: This trial suggests that there is an economic advantage to using the YEARS rule combined with the PERC rule and the age-adjusted D-dimer threshold in PERC-positive patients, as this strategy is non-inferior and less costly than the standard diagnostic strategy. Trial registration number ClinicalTrials.gov Identifier: NCT04032769; July 25, 2019