CHA2DS2-VASc score influences the outcome in stroke patients with or without atrial fibrillation (AF). We assessed whether the risk stratification based on the prestroke CHA2DS2-VASc score may predict the response to intravenous (IV) thrombolysis in stroke patients. We conducted an analysis on prospectively collected data of 516 consecutive AF and non-AF patients treated with IV thrombolysis. Outcome measures were major improvement (NIH Stroke Scale [NIHSS] ≤8 points from baseline or NIHSS score 0) and deterioration (death or NIHSS ≥1 points from baseline) or no improvement (NIHSS score equivalent to baseline) at 24 h; excellent (modified Rankin Scale [mRS] score ≤1) and unfavorable outcome (mRS score >2) at 3 months. Multivariate analysis showed that ORs for major improvement and excellent outcome were lower in patients with intermediate risk (CHA2DS2-VASc = 1) (OR 0.39, 95 % CI 0.16-0.92, p = 0.032; OR 0.10, 95 % CI 0.02-0.56, p = 0.009), moderately high risk (CHA2DS2-VASc = 2) (OR 0.43, 95 % CI 0.19-0.96, p = 0.040; OR 0.16, 95 % CI 0.03-0.76, p = 0.022), and very high risk (CHA2DS2-VASc > 3) (OR 0.31, 95 % CI 0.15-0.65, p = 0.002; OR 0.17, 95 % CI 0.04-0.81, p = 0.026), whereas ORs for deterioration or no improvement and unfavorable outcome were higher only in patients with very high risk (OR 4.26, 95 % CI 1.24-14.65, p = 0.021; OR 9.26, 95 % CI 1.15-74.65, p = 0.037), compared with low risk (CHA2DS2-VASc = 0). Low-risk level based on the prestroke CHA2DS2-VASc score was predictor of effective response to IV thrombolysis. Very high-risk level was predictor of failed response, compared with low-risk level.