Seven patients with venous thrombosis and contraindications to traditional thrombolytic therapy, consisting of recent intracranial surgery, recent pineal or retroperitoneal hemorrhage, active genitourinary or gastrointestinal bleeding, epidural procedures, and impending surgery, were successfully treated with a modified thrombolytic regimen. To improve safety, prolonged continuous infusions of tissue plasminogen activator (tPA) was eliminated in favor of once-daily low-dose intraclot injections of tPA to minimize the amount and duration of tPA in the systemic circulation, and low-therapeutic or regional anticoagulation was used to reduce anticoagulant risks. These modifications may allow thrombolytic treatment for selected patients with severe venous thrombosis who are deemed to be at high risk.