Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor (PAC1) play a critical role in biological processes that mediate stress response and have been implicated in psychological outcome following trauma. Our previous work [Ressler et al. (2011); Nature 470:492–497] demonstrated that a variant, rs2267735, in the gene encoding PAC1 (ADCYAP1R1) is associated with post-traumatic stress disorder (PTSD) in a primarily African-American cohort of highly traumatized females. We sought to extend and replicate our previous finding in a similarly trauma-exposed, replicate sample of 1,160 African-American adult male and female patients. Self-reported psychiatric measures were collected, and DNA was obtained for genetic analysis. Using linear regression models to test for association with PTSD symptom severity under an additive (allelic) model, we found a genotype × trauma interaction in females (P < 0.001), but not males (P > 0.1); however, there was no main effect of genotype as in our previous study. The observed interaction suggests a genetic association that increases with the degree of trauma exposure in females only. This interaction remained significant in females, but not males, after controlling for age (P < 0.001), income (P < 0.01), past substance abuse (P < 0.001), depression severity (P = 0.02), or child abuse (P < 0.0005), and all five combined (P = 0.01). No significant effects of genotype (or interactions) were found when modeling depression severity when controlling for comorbid PTSD symptom severity (P > 0.1), demonstrating the relative specificity of this variant for PTSD symptoms. A meta-analysis with the previously reported African-American samples revealed a strong association between PTSD symptom severity and the interaction between trauma and genotype in females (N = 1424, P < 0.0001). © 2013 Wiley Periodicals, Inc.