We previously reported that CGRP plays a critical role in reduction of stress-induced gastric mucosal injury by increasing gastric prostacyclin (PGI₂) levels in rats. Estrogen has been shown to increase the production of CGRP in sensory neurons. Isoflavone has estrogen-like effects, and is referred to as a phytoestrogen. Thus, we hypothesized that estrogen and isoflavone might inhibit ovariectomy (OVX)-induced decreases in gastric tissue levels of CGRP, thereby attenuating gastric mucosal injury. We examined these possibilities in the present study. Administration of estradiol (EST) and isoflavone for 4 weeks completely reversed OVX-induced decreases in CGRP mRNA levels of dorsal root ganglion neurons (DRG) in rats. OVX-induced decreases in gastric tissue levels of CGRP and 6-keto-PGF₁, a stable metabolite of PGI₂, in rats were reversed by EST and isoflavone. Water -immersion restraint stress (WIR)-induced increases in gastric tissue levels of CGRP and 6-keto-PGF₁ were inhibited in ovariectomized rats. This inhibition was completely reversed by EST and was partially, but significantly, reversed by isoflavone. WIR-induced gastric mucosal injury was exacerbated by OVX, which was reversed by EST and isofolavone. In vitro experiments using DRG isolated from rats demonstrated that neither EST nor isoflavone enhanced CGRP release from DRGs, but the former enhanced it in the presence of anandamide, an endogenous agonist for vanilloid receptor-1. These observations suggested that estrogen and isoflavone might inhibit OVX-induced decreases in CGRP levels in DRG by promoting transcription, thereby contributing to attenuation of stress-induced gastric mucosal injury in ovariectomized rats.