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Whether patients with small perfusion lesions benefit from thrombolysis remains an uncertainty. We assessed acute ischemic stroke patients with a total perfusion lesion of <15 mL and tested the hypothesis the pattern of corticospinal tract (CST) involvement might predict outcome in thrombolysis-eligible patients.We used a prospectively collected cohort of acute ischemic stroke patients being assessed for thrombolysis at 7 centers. Three neurologists categorized the presence of hypoperfusion and infarction within CST. Excellent outcome was defined as 90-day modified Rankin Scale score 0 to 1.Of 2654 patients, 407 had a perfusion lesion <15 mL and were clinically eligible for thrombolysis (243 being treated). Median National Institutes of Health Stroke Scale was 5.0, and 312 (76.7%) patients achieved excellent outcome. Alteplase treatment was an independent unfavorable factor for excellent outcome (alteplase-treated 72.0% versus untreated 83.5%; odds ratio, 0.541; P=0.025). For patients with CST hypoperfusion without CST infarction, alteplase treatment was an independent favorable factor for excellent outcome (alteplase-treated 75.6% versus untreated 47.1%; odds ratio, 4.096; P=0.045). Among patients with CST infarction, alteplase treatment was an independent unfavorable factor for excellent outcome (alteplase-treated 30.6% versus untreated 88.9%; odds ratio, 0.002; P=0.003). Among patients without either CST hypoperfusion or CST infarction, alteplase treatment was not an independent influencing factor for excellent outcome (alteplase-treated 80.1% versus untreated 87.7%; P=0.258).Only patients with CST hypoperfusion without CST infarction among eligible acute ischemic stroke patients with small perfusion lesions could benefit from thrombolysis, which needs to be confirmed in future prospective studies. Patient selection, including an assessment of lesion location rather than purely lesion volume, may be ideal.