Acute renal vein thrombosis (RVT) is a rare but noteworthy form of venous thromboembolism. Traditional management has been systemic anticoagulation with heparin, followed by warfarin. We report a case of acute RVT with multiple pulmonary emboli that occurred in a 40-year-old woman who was taking oral contraceptives and was subsequently found to have protein S deficiency. The patient was treated with catheter-directed thrombolysis, and complete resolution of the RVT was achieved. This case suggests that oral contraceptive use in a patient with protein S deficiency may interact in a synergistic manner in the pathogenesis of thrombosis. Also, we believe that catheter-directed thrombolysis is warranted in selective cases in the absence of overriding contraindications.