An inherited or acquired deficiency of protein S leads to a prothrombotic state, with predisposition to venous thrombosis. We describe a case of cerebral venous sinus thrombosis (CVST) associated with acquired protein S deficiency and recanalisation within 15 days of anticoagulation. A 38-year-old man presented with recurrent headache, vomiting, altered sensorium and one episode of transient left hemiparesis. Magnetic resonance venography showed poor flow in the deep cerebral venous sinuses with extensive collateral venous channel formation, which resolved after 15 days of anticoagulation, along with clinical improvement. Serum protein S activity was found to be markedly low (16% of biological reference). CVST should be suspected in a patient with acute features of raised intracranial pressure or focal neurological deficit, and a patient without obvious clinical predisposition for a prothrombotic state should be evaluated for underlying thrombophilic states like protein S deficiency.