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Background: Posttraumatic stress disorder (PTSD) is associated with structural and functional compromise of the anterior cingulate cortex (ACC), which may in turn be associated with impairment of its ability to regulate the amygdala. The Val158Met polymorphism in the catechol-O-methyltransferase gene, which substantially influences dopamine inactivation in the frontal lobe in general and in ACC in particular, may moderate ACC integrity in PTSD., Methods: We tested this hypothesis in a sample of Vietnam and Persian Gulf War veterans who experienced substantial military operational stress, including 51 who met criteria for PTSD and 48 matched controls who did not., Results: Participants with PTSD were previously reported to have smaller ACC volumes than controls in this sample. A novel repeated-measures analysis of variance was conducted with PTSD diagnosis, Val158Met genotype, and their interaction predicting left and right ACC volume. Genotype was not directly related to ACC volume, but it did significantly interact with the PTSD diagnosis. The difference in ACC volume between the participants without PTSD and participants with PTSD was greater among individuals homozygous for the Val allele than among carriers of the Met allele. This finding was driven largely by the right ACC. Analyses of Caucasian-only, non-Caucasian-only, and male-only subsamples indicated similar patterns., Conclusions: Our findings suggest Val158Met genotype moderates the effect of PTSD-related processes on right ACC volume., (Published by Elsevier Inc.)