BACKGROUND Phlegmasia cerulea dolens is an extremely rare condition caused by complete venous occlusion and often results in tissue necrosis, limb amputation, or death. Treatment options include systemic anticoagulation, systemic thrombolytic therapy, fasciotomy, or surgical thrombectomy. Rare case reports have described the use of catheter-directed thrombolysis in the treatment of this condition. Prompt diagnosis and treatment initiation are important to prevent gangrene, amputation, and ultimately death. CASE We report two unusual cases of phlegmasia cerulea dolens that presented in patients with aggressive gynecologic malignancies and who were successfully treated with catheter-directed thrombolytic therapy. CONCLUSION To maximize the opportunity for limb salvage, catheter-directed venous thrombolytic therapy should be considered in the treatment of phlegmasia cerulea dolens that presents in the gynecologic oncology patient.