<p>Despite thromboprophylaxis, neurosurgical patients remain at high post-operative thromboembolic risk, but early diagnosis of deep vein thrombosis (DVT) is challenging. To investigate whether elevated D-dimer levels may assist to diagnose post-surgery DVT in neurosurgical patients. A retrospective observational study was performed involving all patients who received venous ultrasound assessment (US) for suspected DVT, prompted by elevated D-dimer levels observed after neurosurgery. We compared clinical characteristics and D-dimer levels in patients with and without venous thrombosis. Logistic regression analysis was used to ascertain any association between elevated D-dimer levels and the risk of developing DVT in patients investigated between the 3rd and 15th day after surgery. The ROC curve was used to identify the cut-offs values for suspected DVT. Among 556 consecutive neurosurgical patients, 73 underwent post-surgery venous US for increased D-dimer levels and 35 had venous thrombosis; among these, DVT occurred in 20 out of 43 (46.5%) patients investigated between the 3rd and 15th post-operative day. Among variables considered, only D-dimer levels were significantly higher in patients with DVT. Logistic regression analysis revealed an odds ratio (OR) of 1.98 (CI 1.04–3.78, <i>p</i> = 0.03) for each 1000&#xa0;µg/L D-dimer increase. The ROC curve identified an optimal D-dimer cut-off value of 1334&#xa0;µg/L (sensitivity 0.90, specificity 0.52, negative likelihood ratio 0.2) (OR 9.8, CI 1.8–5.7, <i>p</i> = 0.007). D-dimer threshold of 2200&#xa0;µg/L was associated with the best positive predictive value (77%; specificity 0.87, positive likelihood ratio 3.8). Elevated D-dimer levels were associated with increased risk of DVT after neurosurgery.</p> Graphical Abstract <p>Association between elevated D-dimer levels and deep vein thrombosis following neurosurgery</p> <p></p>