Background: Brain atrophy has shown a protective effect on the risk of early neurological deterioration (END) related to malignant edema in patients with hemispheric infarction but could be deleterious on the outcome. Aims: We aimed to assess whether brain atrophy has an impact on the risk of END and on the outcome in severe ischemic strokes after intravenous (IV) thrombolysis. Methods: From a prospective thrombolysis registry, 137 patients who had a National Institutes of Health Stroke Scale (NIHSS) ≥15, MRI at admission, and IV thrombolysis were included. Relative cerebral volume was calculated. END was defined as a ≥2-points deterioration 72-h NIHSS and a good outcome as a modified Rankin Scale (mRS) ≤2 at 3 months. A multiple logistic regression analysis with a stepwise backward procedure was performed. Results: END and a good outcome were observed, respectively, in 20 (14.6%) and 48 (37.5%) patients. In univariate analysis, predictors of END included age (p = 0.049), diabetes (p = 0.041), and parenchymal hemorrhage (p = 0.039). In multivariate analysis, age (p = 0.018) was significantly associated with END. Brain atrophy was not associated with END even in subgroup analysis according to the baseline infarct size. In univariate analysis, age (p = 0.003), prestroke mRS (p = 0.002), hypertension (p = 0.006), baseline NIHSS (p = 0.002), END (p = 0.002), proximal occlusion (p = 0.006), and recanalization at 24 h (p < 0.001) were associated with a good outcome. Only baseline NIHSS (p = 0.006) was associated with a good outcome after adjustment. Conclusions: We did not find any impact of brain atrophy on the risk of END and the outcome at 3 months in severe ischemic strokes after IV thrombolysis.