Summary:The possibility that cortical spreading depres sion (CSD) may have neuroprotective action during sub sequent focal cerebral ischemia was examined in rats. Three days before the imposition of focal cerebral isch emia CSDs were elicited by applying potassium chloride (KC!) for 2 h through a microdialysis probe implanted in the occipital cortex. Control animals were handled iden tically except that saline was infused instead of KCI. Fo cal ischemia was produced by the intraluminal suture method and cortical and subcortical infarct volumes were measured 7 days later. Neocortical infarct volume was reduced from 124. 8 ± 49. 5 mm 3 in the controls to 62.9 ± Cortical spreading depression (CSD) is character ized by a propagating wave of depressed electrical activity and cell membrane depolarization. It can be elicited by a variety of means including a stab wound, ischemia, raised extracellular potassium, and strong electrical stimulation. It is also known that periinfarct depolarization occurs in cortical tis sue surrounding an acute ischemic lesion (Neder gaard and Astrup, 1986). Because CSD is a process that leads to substantial activation of energy requir ing metabolism (Csiba et al., 1985;Kocher, 1990;Mayevsky and Weiss, 1991), its occurrence in the peripheral zone of an occluded cerebral artery is considered harmful because it can add metabolic stress to the periinfarct region and tip the balance in favor of cell death instead of reversible injury. Recently, Mies et al. (1993) and Chen et al. (1993) have reported that the number of peri infarct depo-