Introduction: Density of hyperdense middle cerebral artery sign (HMCAS) quantified via Hounsfield units (HU) on CT may predict clot composition and stroke TOAST subtype, with clots from cardioembolism displaying lower HMCAS densities due to fibrin predominance than erythrocyte-dominant clots originating from large artery atherosclerosis (LAA). Hypothesis: We hypothesized that embolic stroke of undetermined source (ESUS) is linked to higher density of HMCAS due to its high probability of a cardiac source and that HMCAS as a surrogate marker of clot composition predicts successful reperfusion following endovascular therapy (EVT). Methods: We analyzed data from an ongoing prospective observational study (since 01/2016) in consecutive patients with acute ischemic stroke (AIS) undergoing EVT for proximal occlusion of the middle cerebral artery (MCA) detected on CT-angiography and confirmed on digital subtraction angiography. Stroke subtypes were determined according to TOAST and ESUS criteria. On thin-slice (1.5mm) non-contrast CT, a blinded neuroradiologist assessed average and maximum HU values for HMCAS. Multiple regression analyses were undertaken to explore the association of HMCAS density normalized for contralateral MCA (HMCAS ratio) with stroke subtypes and major reperfusion (TICI 2b/3) following EVT. Results: In this interim analysis 110 out of 253 patients were included (55.1% females, ages 74 [64-80], median [IQR], baseline NIHSS 17 [13-20], 76 with IVT before EVT) of which 19 (17.8%) had ESUS, 65 (60.8%) had cardioembolism and 23 (21.5%) had LAA. Density analyses showed HMCAS ratios of 1.26 ± 0.22 (mean ± SD) in the entire cohort with no differences among subgroups (ESUS: 1.19 ± 0.26, LAA: 1.24 ± 0.25, cardioembolic stroke: 1.29 ± 0.19, p = ns), the latter being also true for HMCAS ratios of maximum HU values and absolute HU values (p = ns). On multivariate regression model adjusted for intravenous tPA and onset to groin puncture time, HMCAS average ratio did not predict major reperfusion (per 1-unit HU increase: 2.13; [0.25-18.29], OR [95% CI]) or stroke subtype. Discussion: Density analysis of HMCAS appears not to be helpful in detection of ESUS, diagnostic discrimination between stroke subtypes, or prediction of reperfusion following EVT.