Background: The ‘drip-and-ship’ paradigm denotes a treatment regimen in patients in whom intravenous (IV) recombinant tissue plasminogen activator (rt-PA) is initiated at the emergency department (ED) of a community hospital, followed by transfer within 24 h to a comprehensive stroke center. Although the drip-and-ship paradigm has the potential to increase the number of patients who receive IV rt-PA, comparative outcomes have not been assessed at a population-based level. Methods: Statewide estimates of thrombolysis, associated in-hospital outcomes, and hospitalization charges were obtained from 2008–2009 Minnesota Hospital Association data for all patients hospitalized with a primary diagnosis of ischemic stroke. Patients who were assigned the drip-and-ship code [International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) V45.88] were classified under the drip-and-ship paradigm. Patients who underwent thrombolysis (ICD-9-CM code 99.10) without drip-and-ship code were classified as primary ED arrival. Patient outcomes were analyzed after stratification into patients treated with IV rt-PA through primary ED arrival or drip-and-ship paradigm. Results: Of the 21,024 admissions, 602 (2.86%) received IV rt-PA either through primary ED arrival (n = 473) or the drip-and-ship paradigm (n = 129). IV rt-PA was administered in 30 hospitals, of which 13 hospitals used the drip-and-ship paradigm; the number of patients treated with the drip-and-ship paradigm varied from 1 to 40 between the 13 hospitals. The rates of secondary intracerebral or subarachnoid hemorrhage were higher in patients treated with IV rt-PA through primary ED arrival compared with those treated with the drip-and-ship paradigm (8.5 vs. 3.1%, respectively; p = 0.038). The in-hospital mortality rate was similar among ischemic stroke patients receiving IV rt-PA through primary ED arrival or the drip-and-ship paradigm (5.9 vs. 7.0%, respectively). The mean hospital charges were USD 65,669 for primary ED arrival and USD 47,850 for drip-and-ship-treated patients (p < 0.001). The rate of admission to a certified stroke center as final destination for acute hospitalization was higher in patients treated by drip-and-ship paradigm compared with those treated by primary ED arrival mode (p = 0.015). Conclusions: The results of the drip-and-ship paradigm compare favorably with IV rt-PA treatment through primary ED arrival in this statewide study. Our results support the recommendations of various professional organizations that the drip-and-ship method of IV rt-PA administration for stroke may be an effective option for increasing the utilization of IV rt-PA on a large scale.