Anticoagulation therapy for cerebral venous sinus thrombosis (CVST) with antithrombin (AT) deficiency due to SERPINC1 mutation does not often yield the expected outcomes. Argatroban may be effective for thrombophilia caused by SERPINC1 mutation. However, argatroban resistance deserves attention.We report a case of a 19-year-old man who was admitted to the hospital with sudden headache, nausea, vomiting, and eye swelling for 3 days. Brain MRI on admission showed multifocal CVST.SERPINC1 mutation (exon1, c.40delA: [p.R14Gfs*17]) combined with hereditary AT deficiency (AT activity was 50% [reference range: 80%-120%]) was detected in this patient. A high dose of anticoagulation treatment with argatroban did not improve the activated partial thromboplastin time (APTT) level to the target range (1.5-3 times over the initial baseline level) for this case. We chose adjunctive anticoagulation (argatroban-combined low-molecular-weight heparin), and the APTT gradually reached the target level. At 3-month follow-up, no recurrence of headache or any systemic hemorrhage was found and the ultrasonography of the optic nerve sheath showed normal. Magnetic resonance black blood thrombosis imaging suggested thrombus absorption.Argatroban resistance may be associated with thrombin receptor saturation and deserves attention. The use of adjunctive anticoagulants may be the optimum strategy during acute and subacute phases of CVST with AT deficiency due to SERPINC1 mutation.Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.