Background and Purpose: The efficacy of pharmacological thrombolysis using tissue plasminogen activator (t-PA) depends upon the relative fibrin content of the thrombus. We investigated whether stroke patients with a right-to-left shunt (RLS), whose embolic source was associated with fibrin-rich thrombus formed in the venous system, were more likely to improve dramatically after thrombolytic therapy than those without RLS. Methods: Acute stroke patients treated with t-PA were assessed prospectively to determine the clinical factors associated with “dramatic improvement– after t-PA administration. “dramatic improvement– was defined as a ≥10 point reduction in the total NIHSS score or a total NIHSS score of 0 or 1 at 7 days. The presence of an RLS was determined using contrast transcranial Doppler (c-TCD) within 6 hours of stroke onset. Results: 48 patients (26 males; mean age; 73.0±10.7 years; baseline NIHSS score, 13.4±6.6) were enrolled. Twenty-one patients had dramatic improvement (D group). c-TCD demonstrated an RLS in 17 (35.4%) patients. On multivariate logistic regression analysis using hyperlipidemia, atrial fibrillation, RLS, DWI-ASPECTS (>8), baseline NIHSS score (<10), and glucose (<120mg/dl) as variables with a P<0.1 on univariate analysis, RLS (OR: 5.9; CI: 1.3–27.3, P＝0.022) was the only independent factor associated with dramatic improvement. Conclusion: The presence of an RLS on c-TCD was an independent factor associated with dramatic improvement after t-PA administration.