Neuroticism is associated with greater reactivity to stress and lifetime psychopathology. In the present study we examined the association between neuroticism and regional and total cortical thickness (CT) across the lifespan, accounting for gender. We also assessed interactions among these factors. 450 subjects between 19 and 80 years were included. Participants completed the International Personality Item Pool and a structural MRI scan. Total CT and the mean values of CT in five regions of interest were examined. We also investigated the interaction effect among age, gender and neuroticism on CT. There was no significant association between neuroticism and regional/total CT. A significant interaction between neuroticism, age, and gender on the thickness of the anterior cingulate was found. Women high in neuroticism showed a thinner anterior cingulate cortex than women low in neuroticism, with increasing age. In contrast, men high in neuroticism had a thicker anterior cingulate cortex compared to men low in neuroticism, with increasing age. Overall, high neuroticism was associated with differential cortical thickness in the anterior cingulate among men and women with increasing age.