We aimed to compare the safety and efficacy of intravenous thrombolysis (IVT) with alteplase for anterior circulation stroke (ACS) and posterior circulation stroke (PCS). From a large multicenter prospective registry-the Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China database-all patients who received IVT within 4.5 hours after stroke onset was reviewed. According to the clinical presentations and imaging findings, the eligible patients were divided into ACS and PCS groups. The safety and efficacy outcome measures included post-IVT symptomatic intracranial hemorrhage (sICH), parenchymal hematoma, and all intracranial hemorrhage (aICH) within 7 days, mortality within 90 days, excellent recovery (modified Rankin Scale 0-1), and functional independence (modified Rankin Scale 0-2) at 90 days. For comparing the outcomes between both groups, the odds ratios (ORs) with 95% confidence intervals (CIs) and the adjusted ORs with 95% CIs were analyzed by univariate and multivariate logistic regression models. Of 953 patients enrolled, 829 patients had ACS and 124 had PCS. The patients with PCS had less often atrial fibrillation (11.3% vs 19.8%; P = 0.02), higher blood glucose level (8.31 vs 7.63 mmol/L; P = 0.02), and more white blood cell counts (8.79 vs 7.75 × 10/L; P = 0.001) than those with ACS. After adjustment for the potential confounders, multivariate logistic analysis showed that PCS patients had not only lower rates of sICH (3.2% vs 7.7%; OR 0.28, 95% CI 0.09-0.90), parenchymal hematoma (1.6% vs 9.2%; OR 0.13, 95% CI 0.03-0.57), and aICH (8.1% vs 20.4%; OR 0.26, 95% CI 0.12-0.54), but also higher proportions of excellent recovery (55.7% vs 41.6%; OR 2.27, 95% CI 1.42-3.61) and functional independence (63.9% vs 53.0%; OR 2.33, 95% CI 1.40-3.89) compared with ACS patients. However, there was no significant difference in the occurrence of mortality (OR 0.86, 95% CI 0.39-1.91) between both groups in the multivariate model, although more PCS patients seemed to die within 90 days than did ACS patients (15.6% vs 10.1%; OR 1.64, 95% CI 0.96-2.82) in the univariate analysis. Our study suggests that IVT with alteplase is more safe and effective for PCS.