Background D-dimer measurement improves the rule-out of thromboembolic disease. However, little is known about the risk of false positive results for the diagnosis of thromboembolic disease and its prognostic value. Herein, we investigated factors influencing the accuracy of D-dimer and its prognostic value in a large cohort of emergency department (ED) patients. Methods This is a secondary analysis of a prospective observational single center, cohort study. Consecutive patients, for whom a D-dimer test was requested by the treating physician, were included. Associations of clinical parameters on admission with false positive D-dimer results for the diagnosis of thromboembolic disease were investigated with logistic regression analysis. Results A total of 3301 patients were included, of which 203 (6.1%) had confirmed thromboembolic disease. The negative and positive predictive values of the D-dimer test at the 0.5 mg/L cut-off were 99.9% and 11.4%, respectively. Several factors were associated with positive D-dimer results potentially falsely indicating thromboembolic disease in multivariate analysis including advanced age (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.04–1.05, p < 0.001), congestive heart failure (CHF) (OR 2.79, 95% CI 1.77–4.4, p < 0.01), renal failure (OR 2.00, 95% CI 1.23–3.24, p = 0.005), history of malignancy (OR 2.6, 95% CI 1.57–4.31, p < 0.001), C-reactive protein (CRP) (OR 1.02, 95% CI 1.01–1.02, p < 0.001) and glomerular filtration rate (GFR) (OR 0.99, 95% CI 0.99–1.00, p = 0.003). Regarding its prognostic value, D-dimer was associated with a 30-day mortality (adjusted OR 1.05, 95% CI 1.02–1.09, p = 0.003) with an area under the curve (AUC) of 0.79. Conclusions While D-dimer allows an accurate rule-out of thromboembolic disease, its positive predictive value in routine ED patients is limited and largely influenced by age, comorbidities and acute disease factors. The strong prognostic value of D-dimer in this population warrants further investigation.