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Although recent research has begun to describe the neural and genetic processes underlying variability in responses to trauma, less is known about how these processes interact. We addressed this issue by using functional magnetic resonance imaging to examine the relationship between posttraumatic stress symptomatology (PTSS), a common genetic polymorphism of the serotonin transporter [5-HTT (5-hydroxy tryptamine)] gene and neural activity in response to viewing images associated with the 9/11 terrorist attack among a rare sample of high-exposure 9/11 survivors (n = 17). Participants varied in whether they carried a copy of the short allele in the promoter region of the 5-HTT gene. During scanning, participants viewed images of the 9/11 attack, non-9/11 negative and neutral images. Three key findings are reported. First, carriers of the short allele displayed higher levels of PTSS. Second, both PTSS and the presence of the short allele correlated negatively with activity in a network of cortical midline regions (e.g. the retrosplenal and more posterior cingulate cortices (PCCs)) implicated in episodic memories and self-reflection when viewing 9/11 vs non-9/11 negative control images. Finally, exploratory analyses indicated that PCC activity mediated the relationship between genotype and PTSS. These results highlight the role of PCC in distress following trauma.