There is still a considerable uncertainty concerning D-dimer cut-off values used in exclusion of venous thromboembolic (venous thromboembolism, VTE) disease, especially among the elderly patients. The objectives were to compare five different D-dimer reagents in the daily practice of an emergency department and to test retrospectively the performances of an age-adjusted cut-off. A total of 473 consecutive ambulatory outpatients suspected of VTE (confirmed VTE = 21) were included in this study. Five commercially available tests were assessed: STA-Liatest D-Di (LI), AxSYM-D-Dimer (AX), VIDAS D-Dimer (VI), INNOVANCE D-Dimer (IN), and HemosIL D-Dimer HS (HS). When using a cut-off value of 500 ng/ml fibrinogen equivalent units (FEUs), D-dimer reagents differ in their abilities to avoid further testing. Indeed, LI allowed exclusion of VTE diagnosis in statistically more patients than VI, AX, and IN but not HS. The use of an age-adjusted cut-off is cost-effective without increasing significantly the number of false negative results. The interest of such strategy is more or less pronounced, depending on the type of D-dimer reagent. The application of an age-adjusted cut-off may be useful to reduce differences among D-dimer reagents to lower costly imaging studies. Prospective validation studies on large cohorts of patients are required to determine the safety of such strategy.