Background and Purpose-A change in acute-to-chronic lesion volume has been proposed as a biomarker for stroke therapies. The objectives of this study were to determine the magnitude of lesion volume change after standard treatment with tissue plasminogen activator and to determine whether specific volume change thresholds can discriminate clinical responders from nonresponders. Methods-We measured lesion volume on diffusion weighted at baseline and on 90-day fluid attenuated inversion recovery MRI and scored 3-month modified Rankin Scale in consecutive patients treated with tissue plasminogen activator. We identified variables associated with excellent (modified Rankin Scale 0 to 1) and independent (modified Rankin Scale 0 to 2) outcomes. Results-We included 53 patients (mean age 69 years, median baseline National Institutes of Health Stroke Scale score 7). The mean acute-to-chronic lesion volume increase was 11.7 (Ϯ7.7) cm 3 . In 23 patients, the chronic lesion was smaller than the baseline lesion. At 3 months, 32 patients had an excellent clinical outcome. Dichotomous volume change variables associated with outcome included decrease in volume Ն30% (Pϭ0.004) and volume increase Ն5 cm