Different brain regions exhibit differing sensitivities to ischemia/excitotoxicity. Whether these differences are due to perfusion or intrinsic factors has not been established. Herein, we found no apparent association between sensitivity to ischemia/excitotoxicity and the level of expression or basal phosphorylation of calcium/calmodulin-stimulated protein kinase II (αCaMKII) or glutamate receptors. However, we demonstrated significant differences in CaMKII-mediated responses after ischemia/excitotoxic stimulation in striatum and cortex. In vivo ischemia and in vitro excitotoxic stimulation produced more rapid phosphorylation of Thr253-αCaMKII in striatum compared with cortex, but equal rates of Thr286-αCaMKII phosphorylation. Phosphorylation by CaMKII of Ser831-GluA1 and Ser1303-GluN2B occurred more rapidly in striatum than in cortex after either stimulus. The differences between brain regions in CaMKII activation and its effects were not accounted for by differences in the expression of αCaMKII, glutamate receptors, or density of synapses. These results implicate intrinsic tissue differences in Thr253-αCaMKII phosphorylation in the differential sensitivities of brain regions to ischemia/excitotoxicity.