Objectives:The current management of acute ischemic stroke is intravenous (IV) recombinant tissue plasminogen activator (rtPA). The presence of a hyperdense middle cerebral artery sign (HMCAS) on pre-treatment head computed tomogram (CT) is considered a poor prognostic sign. We compared the clinical outcome in IV rtPA-treated patients with and without a HMCAS.Design:Retrospective analysis of prospectively collected cases treated with IV rtPA within three hours. Inclusion criteria were the presence of: i) an anterior circulation stroke; ii) a pre-treatment CT available; iii) a pre-treatment National Institutes of Health (NIH) stroke scale (NIHSS) score; and iv) a modified Rankin Score (mRS) at three months.Results:One hundred and thirty patients were eligible for the analysis, 64 (49%) had a HMCAS. The HMCAS group had a trend toward a higher mean (±SD) pre-treatment NIHSS score compared to the non-HMCAS group (13.9±6 vs. 12.2±6; p=0.12). Accordingly, there were more patients with severe strokes (NIHSS>10) in the HMCAS group compared to the non-HMCAS one (48/64=75% vs. 35/66=53%; p=0.009). The mean (±SD) NIHSS score 24 hours after treatment was 10.6 (±8) in the HMCAS group and 8.3 (±7) in the non-HMCAS group (p=0.08). In a multiple logistic regression analysis, the only independent predictor of poor outcome (mRS 3-6) was pre-treatment NIHSS score (p<0.001).Conclusion:Patients with a HMCAS receiving IV rtPA did not fare worse at three months despite a greater proportion of patients with more severe strokes. Based on the current knowledge, IV rtPA remains a good treatment for patients with a HMCAS within three hours of symptom onset.