<p>Avoidance behavior is a prominent and impairing feature of anxiety disorders, trauma- and stressor-related disorders, and obsessive-compulsive disorder. A transdiagnostic approach to identifying the neural basis of avoidance is a promising avenue to shed light on the heterogeneity among individuals affected by these conditions, collectively termed anxiety-related disorders (ARDs). In this cross-sectional study, 58 adults with ARDs and 77 healthy comparisons (HC) completed self-report measures of anxiety sensitivity (i.e., “fear of fear”) and intolerance of uncertainty (i.e., “fear of the unknown”), two transdiagnostic correlates of ARDs. Participants then completed an avoidance task during functional magnetic resonance imaging (fMRI), involving a threat cue paired with shock, safety cues, and safe generalization stimuli with varying resemblance to the threat cue. We examined neural activity preceding avoidance decisions in two phases: a) threat reactivity and b) mental simulation. Threat reactivity in anterior insula and dorsomedial prefrontal cortex tracked threat-relevance of stimuli, as expected. ARD status and anxiety sensitivity both strengthened the relationship of threat reactivity in right and left anterior insula with maladaptive avoidance. We then applied multi-voxel pattern analysis (MVPA) to decode avoidance behavior from neural activity during mental simulation. For those with higher intolerance of uncertainty, avoidance behavior was less concordant with neural activity in motor cortex and intraparietal sulcus. Our results suggest that anxiety sensitivity and intolerance of uncertainty differentially alter the neural mechanisms of avoidance behavior in anxiety-related psychopathology, potentially warranting distinct intervention strategies.</p>