Background: Although the request for D-dimer is widespread in emergency departments (EDs), the causes of elevation and their relationship with D-dimer levels in patients with diagnostic values are uncertain. Methods: In this retrospective investigation, the study population consisted of all patients who visited our large urban ED in the year 2012, for whom a D-dimer test was requested for excluding or diagnosing venous thromboembolism (VTE). Only patients with D-dimer values > 243 ng/mL were included, regardless of their pre-test clinical probability for VTE. Results: The final study population consisted of 1647 patients. A significant positive correlation was found between age and D-dimer. Infection was the most frequent diagnosis (15.6%), followed by VTE (12.1%), syncope (9.4%), heart failure (8.9%), trauma (8.2%) and cancer (5.8%). D-dimer was higher in patients with VTE than in those with other diagnoses (2541 ng/mL vs 1030 ng/mL; p < 0.001). The frequency of VTE gradually increased from patients with values < 1000 ng/mL to those with D-dimer > 3000 ng/mL (4.1 vs 26.7%; p < 0.001). As compared with D-dimer values < 1000 ng/mL, the Odds Ratio for VTE was 8.5 for values > 3000 ng/mL. Conclusions: These results show that D-dimer lacks specificity for diagnosing VTE, especially in elderly patients admitted to the ED with significant co-morbidities. In older patients, elevated values (> 1000 ng/mL) are more frequently associated with VTE, so the use of higher cut-offs may be advantageous. c 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.