Background Prompt diagnosis of cerebral venous sinus thrombosis is a challenge owing in part to its complex and non-specific early clinical symptoms. Objective This study aims to evaluate the value of clinically useful biomarkers (d-dimer and fibrinogen) for cerebral venous sinus thrombosis prediction. Methods Two-hundred and thirty-three suspected cerebral venous sinus thrombosis patients were enrolled in this prospective study. Thirty-four cases confirmed as cerebral venous sinus thrombosis using imaging modalities, whereas the other 199 cases served as mimic controls. Plasma samples of 34 healthy controls were further collected from age- and gender-matched volunteers. D-dimer and fibrinogen levels of all patients and controls were measured before imaging and treatment. The dynamic D-dimer and fibrinogen levels in cerebral venous sinus thrombosis cases after anticoagulation were monitored for up to 180 consecutive days. Results At admission before treatment the average D-dimer and fibrinogen levels in cerebral venous sinus thrombosis group were 968.9 +/- 160.1 mu g/l and 6.9 +/- 1.3 g/l, both of which were significantly elevated when compared with that of the controls. In cerebral venous sinus thrombosis patients, 94.1% had D-dimer elevation, 73.5% had fibrinogen elevation, and 67.6% had both elevated D-dimer and fibrinogen. During acute phase, the sensitivity and specificity of predicting cerebral venous sinus thrombosis using only d-dimer were 94.1% and 97.5%, whereas that of D-dimer in combination with fibrinogen were 67.6% and 98.9%. After administering anticoagulation, D-dimer levels gradually recovered; however, fibrinogen levels fluctuated with 33.3% of the patients still exhibiting elevated values up until 180 days. Conclusions D-dimer may serve as an important screening tool to determine the urgency of obtaining magnetic resonance imaging/magnetic resonance venography or digital subtraction angiography in patients presenting with clinical symptoms that are suspected of cerebral venous sinus thrombosis. Furthermore, d-dimer in combination with fibrinogen may increase the predictive value of acute cerebral venous sinus thrombosis.