We determined the association of neuronal circuitry with the desire to smoke by acquiring and analyzing functional MRI data. The data were acquired in both abstained and subsequently satiated (by 'natural' cigarette smoking) heavy smokers and also in demographically and intellectually matched nonsmokers. During the acquisition, participants were viewing alternating smoking and nonsmoking images that were interleaved by fixation images. From the results, the activities in the mesocorticolimbic pathway including the orbitofrontal cortex, parahippocampus, hippocampus, and midbrain were significantly negatively correlated with carbon monoxide (CO) levels. In contrast, the activities in the motor area and the posterior cingulate cortex plus precuneus were significantly positively correlated with the CO levels. This is the first study to show that mesocorticolimbic and midbrain activities are strongly associated with CO levels, and therefore, possibly with smoking desire levels because of the strong correlation between CO levels and blood nicotine levels.