BACKGROUND AND PURPOSE: We assessed the safety and efficacy of intravenous thrombolysis (IVT) in acute stroke patients with hyperdense middle cerebral artery sign (HMCAS). PATIENTS AND METHODS: Data from consecutive patients with acute (within 6 h of symptom onset) ischaemic stroke admitted between January 1999 and November 2007, in whom HMCAS was diagnosed on admission CT scan was retrospectively analysed. Seventy-one patients, admitted within the 3-h window, were treated with IVT, whilst further 42, admitted 3-6 h after symptom onset, were not. At 3-month clinical follow-up, outcome, mortality at 3 months and incidence of symptomatic intracranial haemorrhage were evaluated. RESULTS: The two groups were comparable concerning age, stroke risk factors, prior antithrombotic treatment and NIHSS scores on admission. Good outcome (mRS score <or= 1) was observed in 12/71 (17%) patients who were treated with IVT and in 1/42 (2%) patients who were not (P = 0.02). IVT treatment was identified as independent predictor of good outcome (P = 0.05). Mortality was 20% in patients treated with IVT and 12% in remaining patients (P = 0.3). Symptomatic intracranial haemorrhage occurred in 1 patient of each group (2%). CONCLUSIONS: These findings suggest that IVT in patients with HMCAS results in significantly better outcome, without significantly influencing mortality.