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International audience; Background: The present study aimed to classify the relative contributions of four biomechanical factors—the root-end filling material, the apical preparation, the root resection length, and the bone height—on the root stresses of the resected premolar. Methods: A design of experiments approach based on a defined subset of factor combinations was conducted to calculate the influence of each factor and their interactions. Sixteen finite element models were created and analyzed using the von Mises stress criterion. The robustness of the design of experiments was evaluated with nine supplementary models. Results: The current study showed that the factors preparation and bone height had a high influence on root stresses. However, it also revealed that nearly half of the biomechanical impact was missed without considering interactions between factors, particularly between resection and preparation. Conclusions: Design of experiments appears to be a valuable strategy to classify the contributions of biomechanical factors related to endodontics. Imagining all possible interactions and their clinical impact is difficult and can require relying on one’s own experience. This study proposed a statistical method to quantify the mechanical risk when planning apicoectomy. A perspective could be to integrate the equation defined herein in future software to support decision-making.