Background and Aims: The characteristics of clot causing acute ischemic stroke, such as size, content, and location, are among the main determinants of response to intravenous tissue plasminogen activator [IV tPA]. Clot heterogeneity and permeability are under-recognized features that might provide additional information in predicting the efficacy of IV tPA. Methods and Patients: Patients with proximal middle cerebral artery occlusion treated with "IV tPA alone" were included. The mean Hounsfield's unit (HU) value, as objective measure of clot attenuation, and its standard deviation (SD), as proposed measure of clot heterogeneity, were obtained. The difference in HU values between CT Angiography and CT was defined as "clot permeability", or "perviousness'. The size (length and volume-mm3) of pre-clot pouch and occluding clot along with ASPECT score and Maas' silvian and leptomeningeal collateral score were measured. Results: The study included 84 cases (44 women, age: 68 +/- 14 years, pretPA NIHSS: 16 +/- 5). Patients with excellent response to tPA (31%) had lower thrombus volume (37.54 +/- 32.37 versus 63.49 +/- 37.36, P = .009) and heterogeneity (4.05 +/- 1.49 versus 5.35 +/- 2.34, P = .011), along with higher clot permeability (48 +/- 35.48 to 31.32 +/- 18.62, P = .006). However, significance of permeability did not survived in the regression analysis with adjustment for NIHSS (beta:-.296, P = .003); clot volume (beta:-.240, P = .014) and collateral status (beta:.346, P < .001). In patients with good prognosis, clot volume was significantly lower (37.76 +/- 30.08 versus 67.57 +/- 37.83, P < .001), whereas permeability was significantly higher (43.97 +/- 32.33 versus 31.13 +/- 19.01, P = .026). However, this effect did not persist in the regression analysis after adjustment for NIHSS (beta:-.399, P < .001), collateral status (beta:.343, P < .001) and clot volume beta:-.297, P = .001). Clot permeability was significantly higher (45.78 +/- 36.34 versus 33 +/- 20.2, P = .045) and heterogeneity was lower (4.1 +/- 1.55 to 5.27 +/- 2.32, P = .028) in patients with dramatic response to tPA (27%). In patients responding positively to IV tPA (48%), clot permeability was numerically higher (39.85 +/- 31.79 to 33.47 +/- 19.28, P = .268), while clot volume (48.15 +/- 34.5 to 62.07 +/- 39.62, P = .093) was lower. Clot volume, permeability and heterogeneity did not show a significant difference in any (38.1%) or symptomatic (8.3%) bleeders after IV tPA. The chance of IV tPA to be beneficial increased in patients with clot volume lower than 45 mm(3), with an increased likelihood of this benefit to be observed within the first day after IV tPA. Our detailed explorative ROC analysis was not able to detect a volume threshold above which the positive effect of IV tPA disappeared. Conclusion: Clot volume is critical for the effectiveness of IV tPA in acute ischemic stroke. Clot permeability and heterogeneity may modify its effect. CT technologies, which are readily available when evaluating a stroke patient in an emergency setting, provide us with useful parameters regarding the size, permeability and heterogeneity of the clot.