The aim of our study was to compare the rapid neurological improvement after intravenous recombinant tissue-type plasminogen activator (rtPA) in patients with proximal hyperdense middle cerebral artery sign (p-HMCAS) to those without the sign and those with the distal hyperdense middle cerebral artery sign (d-HMCAS). Admission and 24 hour non-contrast CT scans of 120 patients with middle cerebral artery (MCA) territory stroke who were treated with intravenous rtPA were assessed for the presence of p-HMCAS and d-HMCAS. The sign was classified according to the site of occlusion. Rapid neurological improvement was defined as ≥50% improvement in the NIHSS score at 24 hours after thrombolysis. Rapid neurological recovery after thrombolysis was assessed and compared between the subgroups. Rapid neurological recovery was less common in the pooled group of patients with either p-HMCAS or d-HMCAS than those without the sign (p<0.01). Patients with p-HMCAS were less likely to have rapid neurological recovery than those with d-HMCAS (p<0.01). However, there was no difference in early neurological recovery between patients with d-HMCAS and those without any hyperdense sign. Our study showed that poor neurological recovery post rtPA was confined to p-HMCAS and not to d-HMCAS, indicating that these signs have quite different prognostic significance.