Tartrazine is a food color that may adversely affect the nervous system. Vitamin E is a neuro-protective agent. This study aimed to evaluate the effects of tartrazine and vitamin E on the performance of rats in memory and learning tests as well as the structure of medial Prefrontal Cortex (mPFC). The rats were first divided into seven groups which received the followings for a period of seven weeks: distilled water, corn oil, vitamin E (100mg/kg/day), a low dose (50mg/kg/day) and a high dose (50mg/kg/day) of tartrazine with and without vitamin E. Behavioral tests were conducted and the brain was extracted for stereological methods The high dose of tartrazine decreased the exploration time of novel objects (P<0.01). The low and high doses of tartrazine led into an increase in working and reference memory errors in acquisition and retention phases (eight-arm radial maze) compared to distilled water group (P<0.01). Additionally, the high dose of tartrazine induced a reduction in the volume of mPFC (∼13%) and its subdivision. Not only that, but the number of neurons and glial cells (∼14%) as well as the mushroom and thin spines per dendrite length declined. The length of dendrites per neuron also reduced in comparison to the distilled water group (P<0.01). Nonetheless, concomitant treatment of the rats with vitamin E plus tartrazine prevented the above-mentioned changes. An acceptable daily dose of tartrazine could induce impairment in spatial memory and dendrite structure. Moreover, a high dose of tartrazine may defect the visual memory, mPFC structure, the spatial memory and also cause dendrite changes. Vitamin E could prevent the behavioral and structural changes.