Objective: To observe the efficacy and safety of recombinant tissue-type plasminogen activator (rtPA) intravenous thrombolysis (IVT) in the treatment of acute cerebral infarction with hyperdense middle cerebral artery sign (HMCAS). Methods: Acute cerebral infarction patients with HMCAS from July 2010 to November 2015 at the First Affiliated Hospital of Dalian Medical University were collected.These patients were divided into two groups depending on whether they received IVT or not.The Nation Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) were used to evaluate early and long-time therapeutic effects.Efficacy and safety were compared between the two groups. Results: A total of 93 patients were eligible for the analysis, with 45 cases in IVT group and 48 cases in non-IVT group.As time went by, NIHSS score in IVT group showed significant downward trend than the non-IVT group.The rate of patients with good outcome in IVT group was higher than that in non-IVT group (P<0.05). The rate of hemorrhage transformation (HT) in IVT group and non-IVT group was 35.6% (16/45) and 10.4% (11/48), respectively, and the difference was statistically significant (P<0.05). While no statistically significant difference was found about the rate of symptomatic intracranial hemorrhage (sICH) (8.9% vs 2.1%, P>0.05) and mortality (33.3% vs 27.1%, P>0.05) between these two groups.Logistic regression analysis identified relativity between IVT treatment and good outcome (P<0.05), hemorrhage transformation (P<0.05), rather than mortality (P>0.05). Conclusions: Intravenous thrombolysis with rt-PA is an effective and safe treatment for most acute ischemic stroke patients with HMCAS and can promote early neurologic improvement and significantly improve long-term functional prognosis.Although Ⅳ thrombolysis can increase the risk of overall HT, it does not add risk in sICH and mortality.