Introduction: IV rt-PA guidelines exclude therapeutically anticoagulated or thrombocytopenic patients. These exclusion criteria may limit thrombolytic therapy to patients who might benefit, especially with the increased use of novel oral anticoagulants (NOACs). The objective of this study is to determine if IV rt-PA is safe, especially in this patient population. Methods: Retrospective analysis of IV rt-PA treated patients receiving oral anticoagulation (warfarin (INR > 1.7)), novel oral anticoagulant (NOAC), therapeutic heparin, low-molecular weight heparin (LMWH), or with thrombocytopenia (platelets < 100K). Patients were treated using SMART criteria (consent obtained for off label rt-PA use). Safety was evaluated by symptomatic intracerebral hemorrhage (sICH) rate ≤36hr after treatment. Results: 81 patients were identified. 35 patients received therapeutic warfarin and 1 had coagulopathy (unclear etiology); mean INR=2.2 (range 1.7-3). 5 received therapeutic IV heparin, 6 full dose (1 mg/kg BID) LMWH, and 22 therapeutic NOACs. 12 had thrombocytopenia (mean platelet count 77K). There was a consistent increase in NOAC use in this cohort; 25% of the patients were taking NOACs from 2012-14, increasing to 71% from 2015-17. Out of all patients, 7 received intra-arterial (IA) rt-PA, and 8 thrombectomy. There were 3 sICH (3.75%), none in patients taking NOACs; for all sICHs there were mitigating factors that contributed (undiagnosed malignancy, adjunctive IA rt-PA, incorrect time of onset). Two developed hematoma at the catheter site with no clinical effect. Conclusions: These data suggest that IV rt-PA can be safely administered in therapeutically anticoagulated and thrombocytopenic patients, and sICH rates were similar to the NINDS cohort. The use of IV rt-PA in these patients may increase eligibility for acute stroke therapy, particularly where IA therapy is unavailable. Furthermore, preliminary results for patients taking NOACs indicate a good safety profile in this growing subpopulation.