Adaptive behavior requires the ability to react to potentially harmful stimuli, characterized by high negative inherent emotional salience (iES) (e.g., spiders, snakes), and to the unexpected non-occurrence of anticipated events. When presented simultaneously, threatening stimuli and unexpected absence of anticipated outcomes induce distinct electrocortical responses in different time periods. In this study, we used fMRI to test whether processing of the absence of anticipated outcomes (prediction errors) was anatomically dissociated from the processing of iES or whether iES simply modulated activity of areas processing the non-occurrence of anticipated outcomes. Participants saw two alternating pairs of faces and indicated for each pair which one would have a declared target stimulus on its nose. Depending on the condition, the target stimulus was either a spider (high iES stimulus) or a disk (low iES stimulus). The target stimulus switched to the other face after several consecutive correct responses, with the switch being indicated by the appearance of the alternative stimulus (disk when the spider was the declared target; spider when the disk was the declared target). We found that the spider induced stronger activation in visual areas than the disk. By contrast, the absence of anticipated outcomes specifically activated the orbitofrontal cortex (OFC), irrespective of the iES of the outcome stimulus. The findings support a generic role of the OFC in outcome monitoring.