ABSTRACT Low sensation seekers are theorized to avoid risk more often because risk is emotionally more costly for them (in comparison to high sensation seekers). Therefore, individual differences in sensation seeking should predict differences in risk task–induced cortisol changes. Furthermore, the neural mediation that accounts for the relation between sensation seeking and cortisol changes has not been studied. The current study tested whether individual differences in sensation seeking predicted cortisol changes in relation to a risk task and whether this relation was mediated by frontal lobe activation. Participants (N=17) who varied in sensation seeking completed an fMRI study in which they rated the likelihood they would take various risks. Cortisol was measured from saliva samples collected prior to and after the fMRI procedure. The findings show that low sensation seekers showed the greatest rise in cortisol after the risk procedure, and this relation was partially mediated by increased orbitofrontal cortex activity.