Polymorphisms in the RGS2 (regulator of G-protein signaling 2) gene were found to be associated with anxious behavior in mice and anxiety in humans. We examined whether rs4606, a single nucleotide polymorphism (SNP) of RGS2, and social support moderated risk for PTSD in an epidemiologic sample. The study examines 607 adults from the 2004 Florida Hurricanes study who returned buccal DNA samples via mail. rs4606 was associated with increased symptoms of posthurricane PTSD symptoms under conditions of high hurricane exposure and low social support (P<.05). Further, this polymorphism was associated with lifetime PTSD symptoms under conditions of lifetime exposure to a potentially traumatic event, and low social support (P<.001). These gene by environment interactions remained significant after adjustment for sex, ancestry, and age. RGS2 rs4606 modifies risk of postdisaster and lifetime PTSD symptoms under conditions of high stressor exposure. This is the first demonstration of gene-environment interaction for this locus.