Current evidence indicates that, although African Americans (AA) are more likely to attempt to quit smoking than Caucasians (CC) in any given year, success rates are lower for AA. However, factors contributing to these differences are not well known. In order to explore potential factors, this study assessed differences in attention to smoking cues between ethnic groups. Participants underwent morning functional magnetic resonance imaging scanning while viewing images of AA models and CC models who were either smoking (smoking cues) or engaging in everyday activities (neutral cues), interspersed with a fixation baseline period. The study was conducted at the Hoglund Brain Imaging Center of the University of Kansas Medical Center in Kansas City, KS. We studied 17 smokers (eight AA, nine CC) after 12-hour abstinence and 17 non-smokers (eight AA, nine CC) matched by age, gender, years of education, and handedness. The AA and CC smoking groups were also matched for number of cigarettes smoked per day. All results are P < 0.01, corrected for whole brain. There was a strong ethnicity by condition interaction among smokers in several a priori regions of interest. AA smokers showed a greater increase in response to smoking (versus neutral cues) than CC smokers in the medial prefrontal cortex, right lateral orbitofrontal cortex, and bilateral ventrolateral prefrontal cortex. In smoking versus baseline contrasts, additional areas of greater activation were found in AA, including the right amygdala and left caudate nucleus. No significant differences in cue-elicited brain activation were found between AA and CC non-smokers. These preliminary findings demonstrate variation in brain activation in response to smoking cues between AA and CC smokers in structures known to be associated with nicotine addiction. Differences in neural response may reflect fundamental differences in attention to smoking cues, which may in turn contribute to differences in effectiveness of nicotine dependence treatments among ethnic populations.