Three different slow potential (SP) changes resulting from focal brain injury are described. The first is an immediate, high amplitude (in excess of 25 mV) negative shift at the site of injury. The second is a biphasic negative-positive SP wave which spreads throughout the cortex ipsilateral to injury and is similar to spreading depression (SD). The third SP change, called here the injury-induced diffuse slow potential (IDSP) is a prolonged (lasting approx. 2 h) negative shift occurring simultaneously in many brain areas, also in those far removed from the injured focus. The SD can be separated from IDSP by the size of focal injury; a 20 μ puncture of the parenchyma will trigger IDSP but not SD. An injury resulting from a larger puncture triggers both, SD and IDSP. IDSP can not be induced by a re-entry of a previously damaged tissue. The magnitude of IDSP has anatomical specificity in that the largest amplitude occurs in white as compared to gray of the cortex or of the caudate nucleus. Also, the magnitude of the hypothalamic IDSP is larger when ipsilateral corpus callosum-commissural regions are injured. Electrical stimulation of the cortex in rats sufficiently strong to result in tonic-clonic convulsions triggers SD and IDSP; these two slow potential changes are similar to those induced by mechanical injury. A transpinnate electrical stimulus strong enough to elicit a grand-mal type of discharge results in a diffuse negative slow potential change similar to IDSP elicited by mechanical damage or direct cortical stimulation.