Catheter-directed thrombolysis (CDT) has emerged as a potential management option for proximal deep vein thrombosis (DVT). Low-dose alteplase with concomitant heparin have traditionally been used in this setting. Patients with heparin-induced thrombocytopenia (HIT) undergoing CDT pose a challenge since heparin would be contraindicated. Robust evidence regarding use of direct thrombin inhibitors (DTI) in these scenarios is lacking. Additionally, there are even fewer data regarding direct intra-catheter DTI administration at the target site during CDT. We describe the case of a 61-year-old female who developed HIT and an extensive right iliofemoral DVT with distal involvement. After obtaining access via the popliteal vein, argatroban 0.8 mcg/kg/min was infused through the venous sheath with a goal aPTT of 40-50 seconds, while intra-catheter alteplase was infused at 1 mg/hr. Post-operatively, both infusions continued for 8 and 18 hours, respectively. Repeat venography showed clot resolution and patency from the common femoral down to the peroneal vein. Residual clot burdens and stenosis were still noted in the lower inferior vena cava and common iliac vein, prompting suction thrombectomy and balloon angioplasty. Argatroban was transitioned back to being infused intravenously. No bleeding complications occurred and an argatroban-to-warfarin bridge was subsequently completed. To our knowledge, this is the first case report to describe direct intra-catheter administration of both argatroban and alteplase during CDT for a patient with HIT who developed an extensive iliofemoral DVT with distal involvement. If clinicians are to opt for direct intra-catheter argatroban administration, we advise individualizing pharmacotherapy with close monitoring of coagulation parameters.