Background and Purpose— Patients with right hemispheric strokes (RHSs) present later to an emergency department, have a lower chance to receive intravenous recombinant tissue plasminogen activator (IV rt-PA), and have worse clinical outcomes than do patients with left hemispheric strokes (LHSs). We analyzed outcomes after IV rt-PA with respect to the side of the affected hemisphere. Methods— A prospective cohort of acute stroke patients was treated with IV rt-PA at the London Health Sciences Centre (December 1998 to March 2003). Differences between patients with RHS and LHS were identified by univariate analysis. Logistic-regression analysis was used to determine a subset of variables independently associated with major neurological improvement at 24 hours and good outcome at 3 months after treatment. Results— Of 219 stroke patients who received IV rt-PA, 165 had hemispheric strokes (68 RHSs and 97 LHSs). Patients with RHSs were less hypertensive ( P =0.001) and had lower pretreatment National Institutes of Health Stroke Scale (NIHSS) scores ( P =0.005). LHS (odds ratio [OR], 2.29; 95% CI, 1.14 to 4.59; P =0.019), age (OR, 0.96; 95% CI, 0.93 to 0.99; P =0.012), and pretreatment NIHSS (OR, 0.83; 95% CI, 0.78 to 0.89; P <0.0001) were independent predictors of 3-month outcome. Female sex (OR, 3; 95% CI, 1.53 to 5.90; P =0.001) and LHS (OR, 2.07; 95% CI, 1.05 to 4.08; P =0.03) were independent predictors of major neurological improvement at 24 hours after IV rt-PA. Conclusions— Despite higher pretreatment NIHSS, patients with LHSs have a 2-fold increased chance of a good outcome 3 months after rt-PA treatment compared with patients with RHSs. This gain can be clinically detected at 24 hours after treatment. These results need to be coupled with neuroimaging and hemodynamic characteristics known to influence stroke outcome.