Background: Whether the think-aloud protocol is a valid measure of thinking remains uncertain. Therefore, we used functional magnetic resonance imaging (fMRI) to investigate potential functional neuroanatomic differences between thinking (answering multiple-choice questions in real time) versus thinking aloud (on review of items). Methods: Board-certified internal medicine physicians underwent formal think-aloud training. Next, they answered validated multiple-choice questions in an fMRI scanner while both answering (thinking) and thinking aloud about the questions, and we compared fMRI images obtained during both periods. Results: Seventeen physicians (15 men and 2 women) participated in the study. Mean physician age was 39.5+7 (range: 32-51 years). The mean number of correct responses was 18.5/32 questions (range: 15-25). Statistically significant differences were found between answering (thinking) and thinking aloud in the following regions: motor cortex, bilateral prefrontal cortex, bilateral cerebellum, and the basal ganglia (p<0.01). Discussion: We identified significant differences between answering and thinking aloud within the motor cortex, prefrontal cortex, cerebellum, and basal ganglia. These differences were by degree (more focal activation in these areas with thinking aloud as opposed to answering). Prefrontal cortex and cerebellum activity was attributable to working memory. Basal ganglia activity was attributed to the reward of answering a question. The identified neuroimaging differences between answering and thinking aloud were expected based on existing theory and research in other fields. These findings add evidence to the notion that the think-aloud protocol is a reasonable measure of thinking.