Object The incidence of deep venous thrombosis (DVT) after craniotomy is reported to be as high as 50%. In outpatients, D-dimer levels of more than 0.5 mg/L indicate venous thromboembolism (VTE, which subsumes DVT and pulmonary embolism [PE]) with a sensitivity of 99.4% and a specificity of 38.2%. However, D-dimer levels are believed to be unreliable in postoperative patients. The authors undertook the present study to test the hypothesis that D-dimer levels would be systematically raised in a postoperative population and to define a feasible threshold for identification of VTE. Methods Doppler ultrasonography of the lower extremity was performed pre- and postoperatively to evaluate for DVT in 101 patients who underwent elective craniotomy. D-dimer levels were assessed preoperatively and on the 3rd, 7th, and 10th days after surgery. Statistical analysis was carried out to define a feasible threshold for D-dimer levels. Results D-dimer plasma levels were found to be systematically raised postoperatively, and they differed between patients with and without VTE in a highly significant way. On the 3rd day after surgery, D-dimer levels of more than 2 mg/L indicated VTE with a sensitivity of 95.3% and a specificity of 74.1%, allowing for the definition of a feasible threshold. D-dimer levels of more than 4 mg/L were observed in all patients who had PE during the postoperative period (n = 9). Ventilation time and duration of surgery were identified as highly significant risk factors for the development of VTE. Conclusions Using a threshold of 2 mg/L, D-dimer levels will indicate VTE with a high degree of sensitivity and specificity in patients who have undergone craniotomy. Pulmonary embolism seems to be indicated by even higher D-dimer levels. Given that the development of D-dimer plasma levels in the postoperative period follows a principle that can be predicted and that deviations from it indicate VTE, this principle might be applicable to other types of surgery.