Changes in cytosolic free calcium [( Ca2+]i) in the cat cortex were measured in vivo by indo-1 fluorometry during cerebral ischemia and reperfusion and were correlated to the histopathological ischemic changes. These changes were most pronounced in stroke cases with an increase in [Ca2+]i throughout the ischemic and reperfusion periods. Cases without a [Ca2+]i increase showed no histopathological change in the cortical gyrus in which [Ca2+]i was measured. The data support the hypothesis that an increase in [Ca2+]i during cerebral ischemia and reperfusion leads to neuronal damage.