Background: Generalized anxiety disorder (GAD) is a common and sometimes disabling condition often associated with stressful life events that involve significant loss or danger. The disorder appears moderately heritable. Polymorphisms in the RGS2 (regulator of G-protein signaling 2) gene were recently associated with anxious behavior in mice and panic disorder and trait anxiety in humans. We examined whether rs4606, a single nucleotide polymorphism (SNP) in the 3′ UTR of RGS2, was associated with GAD in an epidemiologic sample of adults exposed to the 2004 Florida Hurricanes. Methods: The sample for the current study is 607 adults from the 2004 Florida Hurricane Study who returned buccal DNA samples via mail. Participants were selected via random digit dial procedures and interviewed via telephone about hurricane exposure, social support, and GAD symptoms. The outcome measure was DSM-IV diagnosis of GAD derived from structured interviews. Results:RGS2 SNP rs4606 was significantly associated with GAD in this sample. In logistic regression analyses, each C allele was associated with a 100% (P=.026) increased risk of GAD after controlling for age, sex, ancestry, hurricane exposure, and social support. Conclusions: These findings are consistent with a previously published study showing a higher prevalence of the C allele among panic disorder patients than controls. This study points toward a relevant polymorphism for GAD at the 3′ end of the RGS2 gene; and suggests that studying a recently disaster-exposed sample is both feasible and may improve power to find gene–disorder associations. Depression and Anxiety, 2009. Published 2008 Wiley-Liss, Inc.