Rationale After a cerebral vein thrombosis, there is an increased risk of further venous thromboembolic events. The optimal duration of anticoagulation after cerebral vein thrombosis is unknown. Aim To compare efficacy and safety of a policy of short- (3-6 months) versus long-term (12 months) anticoagulation (any type venous thromboembolic events) after cerebral vein thrombosis for the prevention of venous thromboembolic events. Sample size estimates A sample of 1428 patients (749 per arm) allows detecting a reduction from 10 to 5% in the risk of venous thromboembolic event recurrence with 80% power at 5% significance, with 3% dropout rate. Methods and design An international multicenter, prospective cluster-randomized trial with equal allocation between both interventions (ISRCTN25644448). Each cluster is a participating center, which accepted to be randomly allocated to one of the anticoagulation policies. Eligible patients are adults with radiologically confirmed cerebral vein thrombosis within 30 days, and stable to initiate post-acute anticoagulation. Patients judged by the investigator to be an absolute indication for permanent anticoagulation are excluded. Follow-up is at 6, 12 and 24 months. Study outcomes Primary efficacy outcome is any symptomatic and confirmed fatal/nonfatal venous thromboembolic event (recurrent-cerebral vein thrombosis or non-cerebral venous thromboembolic event). Primary safety outcomes include bleeding events during treatment periods and death from any cause. Discussion This study responds to a knowledge gap in the post-acute management of cerebral vein thrombosis patients by comparing short- versus long-term anticoagulation for the prevention of venous thromboembolic event recurrence.