Interstitial cystitis/painful bladder syndrome is a disease seen mostly in women, and symptoms tend to be worse premenopausally or during ovulation. The four cardinal symptoms of interstitial cystitis/painful bladder syndrome are bladder pain, urgency, frequency, and nocturia. Estrogen has been implicated in the etiology of this disease, but the role of the two estrogen receptors (ER), ERalpha and ERbeta, has not been investigated. We found that, in the bladders of WT mice, ERbeta is expressed in the basal cell layer of the urothelium. Bladders of male ERbeta(-/-) mice were intact and morphologically indistinguishable from those of their WT littermates. However, in female ERbeta(-/-) mice, there was ulceration and atrophy of bladder urothelium concomitant with infiltration of gammadelta T cells concentrated in the areas of atrophy and shedding of urothelium. The data support the idea that activated gammadelta T cells are causing the damage to the urothelium. The hyperactivity of T cells may be because of an imbalance between ERalpha and ERbeta signaling in female ERbeta(-/-) mice. Our data suggest that reduced ERbeta signaling might have a role in the pathogenesis of interstitial cystitis, and ERbeta could be a candidate for a target of medical therapy.