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BACKGROUND Inferior vena cava (IVC) thrombosis is an uncommon complication of deep vein thrombosis and may be associated with a high risk of severe pulmonary embolism, particularly in the presence of free-floating thrombi. Although IVC filter placement may be considered to prevent embolization, prolonged filter dwell increases the risk of recurrent venous thrombosis and reduces retrieval success, highlighting the importance of early thrombus clearance. However, evidence regarding optimal interventional and anticoagulation strategies for IVC thrombosis remains limited. CASE REPORT A 46-year-old woman with Down syndrome and adjustment disorder presented with sudden-onset chest pain and syncope. On admission, she was hypotensive and hypoxemic. Contrast-enhanced computed tomography revealed bilateral pulmonary emboli and a large floating IVC thrombus extending from below the renal vein to the right common iliac vein. A retrievable IVC filter was placed, and anticoagulation was initiated. No underlying thrombophilia was identified. After 2 weeks, regression of the IVC thrombus was insufficient, and catheter-directed thrombolysis with alteplase and heparin was performed, resulting in marked clinical improvement. The patient was discharged on apixaban. After 2.5 months, the pulmonary arterial thrombi had resolved; however, the IVC thrombus persisted. Switching anticoagulation from apixaban to dabigatran led to complete thrombus resolution 4 months after symptom onset, allowing successful retrieval of the IVC filter. CONCLUSIONS This case highlights the potential role of alteplase-based catheter-directed thrombolysis for early thrombus reduction and suggests that switching from a factor Xa inhibitor to a direct thrombin inhibitor may be effective in select patients with refractory IVC thrombosis.