Background and Purpose -Although white matter is a potential target of acute stroke therapy, there is uncertainty about its relative resistance to ischemia and whether it is capable of mounting a penumbral response. To explore these issues further, we examined the differential effects of ischemia on gray and white matter using magnetic resonance (MR) perfusion-diffusion mismatch after acute stroke. Methods -MR imaging studies were performed within 12 hours in patients with initial hemispheric ischemic stroke. “At-risk”tissue was defined as tissue with abnormal diffusion-weighted imaging/perfusion-weight imaging or infarcti on on follow-up image. Tissue was segmented using a probabilistic atlas generat ed from age-matched controls. The proportions of “at-risk”tissue, which was penumbral at the time of imaging, were compared between gray and white matter. R esults -Thirty-two patients had diffusion-perfusion mismatched penumbral tiss ue present in both gray and white matter compartments. Although the absolute mis match volumes were greater in gray (median 42 cm3, interquartile range 18 to 70 cm3)than in white matter (39 cm3, 17 to 49 cm3;P < 0.001), the proportion of “a t-risk”tissue, which was penumbral at the time of imaging (median 3.7 hours, r ange 1.5 to 9.9 hours) was greater in white (69%, 49%to 86%) than gray matter (62%, 52%to 75%; P=0.026). However, the proportions spontaneously salvaged b y 3 months were similar in both compartments. Conclusions -These findings are c onsistent with white matter being able to mount an ischemic penumbral response i n humans and being more resistant to cerebral ischemia than gray matter. They al so raise the possibility that the therapeutic window is longer for white matter and may require alternative therapeutic strategies. Background and Purpose -Although white matter is a potential target of acute stroke therapy, there is uncertainty about its relative resistance to ischemia and whether it is capable of mounting a penumbral response. To explore these issues further, we examined the differential effects of ischemia on gray-white matter using magnetic resonance (MR) perfusion-diffusion mismatch after acute stroke. Methods-MR imaging studies were performed within 12 hours in patients with initial hemispheric ischemic stroke. “At-risk” tissue was defined as tissue with abnormal diffusion- weighted imaging / perfusion-weight imaging or infarcti on on follow-up image. Tissue was segmented using a probabilistic atlas generat ed from age-matched controls. The proportions of “at-risk” tissue, which was penumbral at the time of imaging, were compared between gray and white matter. R esults -Thirty-two patients had diffusion-perfusion mismatched penumbral tiss ue present in both gray and white matter compa rtments. Although the absolute mismatching volumes were greater in gray (median 42 cm3, interquartile range 18 to 70 cm3) than in white matter (39 cm3, 17 to 49 cm3; P <0.001), the proportion of "a t- Tissue, which was penumbral at the time of imaging (median 3.7 hours, average 1.5 to 9.9 hours) was greater in white (69%, 49% to 86%) than gray matter (62%, 52% to 75% P = 0.026). However, the proportions spontaneously salvaged by 3 months were similar in both compartments. Conclusions -These findings are c onsistent with white matter being able to mount an ischemic penumbral response in humans and being more resistant to cerebral ischemia than gray matter They al so raise the possibility that the therapeutic window is longer for white matter and may require alternative therapeutic strategies.