Whether cardiopulmonary bypass alone or together with manipulation of the aorta produces neurologic complications remains controversial. Using a pig model, the immediate effects of aortic cannulation and cardiopulmonary bypass on neural injury in different brain regions were investigated in 3 experimental groups: non-operated controls; operated controls with aortic cannulation without cardiopulmonary bypass; and operated animals undergoing cardiopulmonary bypass. Immunohistochemistry using a monoclonal antibody against calretinin was used to show possible ischemic damage in the hippocampal formation which is one of the most vulnerable regions to ischemia. Both cannulation of the aorta alone and cardiopulmonary bypass resulted in numerous argyrophilic neurons in discrete regions of the prefrontal and cerebellar cortex. Decreased calretinin immunoreaction and a reduced number of calretinin-positive neurons were observed following aortic cannulation or cardiopulmonary bypass compared to the non-operated controls. This suggests that both cannulation of the aorta alone and cardiopulmonary bypass affect a selected population of neurons. Therefore, off-pump, aorta no-touch technique may prevent neurologic complications.