Background The corticotropin releasing hormone (CRH) system has been implicated in a variety of anxiety and mood‐based symptoms and disorders. CRH receptor‐2 (CRHR‐2) plays a role in attenuating biological responses to stressful life events and trauma, making the CRHR‐2 gene a strong candidate to study in relationship to PTSD. Methods The sample was 491 trauma‐exposed white non‐Hispanic veterans and their cohabitating intimate partners assessed via structured interview for lifetime DSM‐IV PTSD; just over 60% met criteria for the disorder. Thirty‐one single nucleotide polymorphisms (SNPs) in and near CRHR‐2, obtained from an array of 2.5 million markers, were tested for association with PTSD diagnosis and symptom severity in the whole sample and in men and women separately. Results Ten SNPs showed nominally significant evidence of association with PTSD in the full sample and two SNPs (rs8192496 and rs2190242) were significant after permutation‐based multiple testing correction (uncorrected ps = .0004 and .0005, odds ratios = .60 and .58, respectively). Analyses stratified by sex revealed that the effect was specific to women, who comprised 35% of the sample (uncorrected ps = .0003 and .0002, odds ratios = .41 and .35, respectively). Two additional SNPs (rs2267715 and rs2284218) also showed significant association with PTSD in women (both uncorrected ps = .001, both odds ratios = .48). Conclusions Results suggest that CRHR‐2 variants may affect risk for PTSD in women by attenuating the stress response and reducing symptoms of the disorder.