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BACKGROUND: Structural deficiencies within the prefrontal cortex might be related to drug-taking behavior that prevails in smokers. Cortical thickness has been found to be a structural modulator of cerebral function and cognition and a subtle correlate of mental disorders. However, to date an analysis of cortical thickness in smokers compared with never-smokers has not been undertaken. METHODS: We acquired high-resolution magnetic resonance imaging scans from 22 smokers and 21 neversmokers and used FreeSurfer to model the gray-white and pial surfaces for each individual cortex to compute the distance between these surfaces to obtain a measure of cortical thickness. The main cortical folds were aligned across individuals with FreeSurfer's surface-based averaging technique to compare whole brain differences in cortical thickness between smokers and never-smokers. RESULTS: Relative to never-smokers, smokers showed greater cortical thinning in the left medial orbitofrontal cortex (mOFC). Cortical thickness measures extracted from mOFC correlated negatively with the amount of cigarettes consumed/day and the magnitude of lifetime exposure to tobacco smoke. CONCLUSIONS: The brains of smokers are structurally different from those of never-smokers in a dosedependent manner. The cortical thinning in mOFC in smokers relative to never-smokers might imply dysfunctions of the brain's reward, impulse control, and decision-making circuits. Related behavioral correlates are suggested to be relevant for smoking initiation and maintenance. Also: Blockade of Nicotine Reward and Reinstatement by Activation of Alpha-Type Peroxisome ProliferatorActivated Receptors http://www.sciencedirect.com/science/journal/00063223 Newsletter of The Italian Society of Tobaccology