The neural correlates of stimulus-independent thoughts (SITs) were investigated in two studies of normal volunteers, using positron emission tomography (PET) and H2(15)O to measure regional cerebral blood flow. Subjects rated how frequently SITs occurred while they were concurrently performing different sets of cognitive tasks. In both studies, the main positive correlations between SITs and blood flow were in the medial prefrontal region. These correlations were not attributable to between-task differences in cognitive demand, or to effects of practice on these demands. An association between medial prefrontal activity and SITs is consistent with data linking this region to self-initiated thought, and its activation during tasks which entail thinking which is decoupled from stimuli in the immediate environment.