Background and Purpose Intracranial thrombi can be characterized according to their permeability as measured by contrast agent penetration. Thrombus composition and its associated pathogenesis are important factors affecting treatment and secondary prevention. We aimed to explore the histopathologic factors explaining the heterogeneity of thrombus permeability measures and evaluated potential correlations with stroke pathogenesis. Methods Thrombus densities were measured in thin-slice noncontrast computed tomography and automatically aligned computed tomographic angiography images of 133 patients with large-vessel occlusions of the middle cerebral artery. Change in thrombus attenuation ((t)) and corrected void fraction (epsilon;attenuation increase corrected for contralateral artery densities) were calculated. First, these thrombus perviousness measures were correlated with histological thrombus components (especially fractions of fibrin-platelet accumulation and red blood cells) and stroke pathogenesis (n=32). For validation, an association between perviousness and pathogenesis was assessed in a second, independent cohort (n=101). Results Thrombus perviousness estimates were correlated with both fibrin/platelets fractions ((t): r=0.43, P=0.016/epsilon: r=0.45, P=0.01) and inversely with red blood cells counts ((t): r=-0.46, P=0.01/epsilon: r=-0.49, P=0.006). In the first cohort, (t) was substantially higher in samples from patients with cardioembolic stroke pathogenesis as compared with noncardioembolic-derived thrombi (P=0.026). In the validation cohort, thrombus perviousness measures differed significantly between cardioembolic ((t): median [ interquartile range]=12.53 [8.70-17.90];epsilon: median [interquartile range]=0.054 [0.036-0.082]) and noncardioembolic thrombi ((t): median [interquartile range]=3.2 [2.17-6.44], P<0.001;epsilon: median [interquartile range]=0.020 [0.011-0.027], P<0.001) and were associated with pathogenesis ((t): =0.45, P=0.016/epsilon: =83.6, P=0.013) in a binary logistic regression model. Conclusions Permeable thrombi showed a strong correlation with lower fractions of red blood cells counts and more fibrin/platelets conglomerations, concurrent with an association with cardioembolic origin. This novel information about thrombus perviousness may be valuable as a new and simple to acquire imaging marker for identifying stroke pathogenesis using early and readily available imaging.