Abstract Background Exposure to psychological stress during combat can lead to posttraumatic stress disorder (PTSD). Anticipation of aversive events is often associated with an intense emotional state in individuals with PTSD. Both the valence (i.e., positive or negative) of the anticipated event and the degree of temporal predictability (i.e., one’s ability to predict when an event will occur) have profound effects on an individual’s emotional experience. This investigation tested the hypothesis that individuals with combat-related PTSD would show increased activation in the insula and related emotion-processing circuitry when anticipating emotionally significant events such as portrayed in combat-related images, and this heighted response within the insula would be particularly enhanced during temporal unpredictability. Methods About 15 male veterans with PTSD and 15 male veterans with combat-exposure but no current or lifetime history of PTSD (combat exposed controls/CEC) performed a temporal unpredictability anticipation task of unpleasant (combat-related) and pleasant images during fMRI. Results As expected, greater activation in the bilateral anterior insulae was observed in the PTSD versus the CEC subjects during anticipation of combat-related images when the anticipatory period was of uncertain duration (p<0.05). Furthermore, activation in the right anterior insula was related to greater perceived threat in the CEC group (ρ=0.619). Limitations The current study looks only at combat-related PTSD in a modest preliminary sized sample. Conclusions These findings suggest that an excessive anticipatory reaction in individuals with PTSD to temporally unpredictable aversive stimulus may relate to greater perceived threat. These findings are concordant with psychological models of PTSD that focus on the association of PTSD with the experience of decreased predictability and control.