Multiple subpial transection (MST) is a new surgical technique for treating seizures that arise from functionally critical cortical areas. It has a reported efficacy comparable to that of standard temporal lobe resections. Although the mechanism through which MST works is unknown, the carefully controlled lesions, placed 5 mm apart at the midlevel of the cortical gyri, could produce fiber damage that would prevent horizontal synchronization and spread of epileptic discharges while allowing normal cortical functions such as those related to movement or speech to be preserved. We studied the acute neuropathological features associated with MST in 8 patients with intractable temporal lobe epilepsy. Transections were made along major temporal gyri just before standard lobectomy was performed. After resection, tissue was processed by conventional histological and immunocytochemical techniques. Macroscopically, subpial transections (STs) were perpendicular to the main gyral axis and had an appropriate spacing. Microscopically, most of the lesions were perpendicular and at midlevel. However, many transections involved the lateral aspects of the small gyri, resulting in oblique or deep STs, some of which reached the gray-white matter junction due to the complex microscopic neocortical architecture, in which small gyri are superimposed on major lobar gyri, and to the variable cortical thickness. Extensive acute pyknosis and tissue edema were also evident adjacent to the transections. These changes were variable and extenDed 1-3 mm laterally as irregular columnar blocks. In the deep lesions, myelin pallor and decreased neurofilament immunoreactivity were observed in the white matter. Based on the distribution of STs and their adjacent parenchymal injury, we conclude that this technique produces block-type lesions that probably disrupt propagation of epileptogenic activity. In most instances, midlevel horizontal fibers are damaged; one third of the cases showed additional deep injury that would sever afferent and efferent axons. Therefore, in addition to horizontal desynchronization, a deafferentation mechanism involving different fiber systems may contribute to the anti-seizure effects of MST. We hypothesize that preservation of cortical function is mediated by cortex remaining in the sulcus and gyral crown and possibly by reorganization of tissue adjacent to transections.