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Introduction: This observational study conducted across seven emergency care units compares the efficacy of four D‐dimer detection methods, namely HemosIL D‐dimer HS (HS), HemosIL D‐dimer HS‐500 (HS‐500), VIDAS D‐dimer (VIDAS), and HemosIL AcuStar D‐dimer (ACUSTAR). The primary focus is on patients with a clinical suspicion of deep venous thrombosis (DVT) or pulmonary embolism (PE). Methods: A total of 149 samples were collected from patients with suspected DVT or PE. The confirmation of DVT/PE was based on calf ultrasound or computed tomography‐Angiography. Direct comparisons were made between the different detection methods, considering both their analytical performance and clinical utility. Additionally, the impact of an age‐adjusted cut‐off on the diagnostic accuracy of each method was assessed. Results: The results revealed comparable negative predictive value, sensitivity, and specificity across the methods, with a notable exception of increased specificity for HS compared with HS‐500 (50.8% vs. 41.5%, p = 0.03). Further analysis incorporating an age‐adjusted cut‐off demonstrated a significant improvement in specificity for HS. When using the age‐adjusted cut‐off, HS exhibited a substantial increase in specificity compared with HS‐500 (63.1% vs. 49.2%, p = 0.004) and demonstrated significantly higher specificity compared with VIDAS (63.1% vs. 53.8%, p = 0.04). Conclusion: The study emphasizes the nonuniversal effect of an age‐adjusted cut‐off and discusses the potential necessity for different cut‐off values, particularly in the case of HS‐500. These findings contribute to the understanding of D‐dimer detection methods in the context of DVT and PE, providing insights into their relative performances and the potential optimization through age‐adjusted cut‐offs. [ABSTRACT FROM AUTHOR]