Abstract Background Objective Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common complication in craniotomy patients and is associated with increased morbidity and mortality. The duration of surgery is a known risk factor. Other factors such as positioning and tumor entity have hardly been investigated or are controversial. In two pilot studies, the determination of plasma D-dimer concentration led to a high detection rate of DVT, while the use of intermittent pneumatic venous compression (IPC) drastically reduced the incidence of VTE. In the present study we investigated the efficacy of the two approaches, either alone or in combination, in a large patient cohort. Methods 1759 patients who underwent elective craniotomy between 2009 and 2023 were retrospectively analyzed. The staggered use of D-dimer determination and intraoperative use of IPC resulted in 3 groups: Group 1: no procedure; Group 2: D-dimer evaluation; Group 3: IPC and D-dimer evaluation. If the D-dimer level was ≥ 2 mg/l (Fibrinogen equivalent units; FEU), venous ultrasound was performed. Age, gender, tumor entity, duration and extent of surgery, patient positioning, type of VTE were also recorded and analyzed. Results The introduction of postoperative D-dimer evaluation increased the rate of detection of thrombosis from 1.7% in group 1 to 22.6% in group 2. The addition of IPC reduced the rate of thrombosis to 4.4%. Age, gender and patient positioning did not affect the rate of VTE. We were able to confirm the duration of surgery as an individual risk factor and showed that WHO grade 4 tumors and metastasis have an increased VTE risk. Conclusions If D-Dimer levels are not analyzed routinely about 20% of craniotomy patients suffer from a clinically silent thrombosis. Each with the risk of fate PE. Intraoperative use of IPC during craniotomy dramatically reduces the risk of VTE.