We have reported previously that a mixture of conjugated estrogens which is effective in shortening the prolonged bleeding time in uremic patients is also effective on bleeding time in a rat model of uremia. With the present study we took advantage from such a rat model of chronic uremia and decided to identify the component(s) of the conjugated estrogen mixture responsible for shortening the bleeding time. Moreover, we wanted to clarify whether estrogen effect on primary hemostasis is due to a receptor mechanism and can be neutralized by specific estrogen receptor antagonists such as tamoxifen or clomiphene. Both estrone sulfate and 17 beta-estradiol, but not equilin, were effective in shortening the prolonged bleeding time of uremic rats. 17 beta-Estradiol was the most active component of the mixture, reproducing the time course of bleeding time shortening of the entire mixture (effect lasting 48 hr). The effect of estrone sulfate injection lasted only 24 hr. Tamoxifen and clomiphene pretreatment prevented the shortening of bleeding time induced by conjugated estrogen mixture and its active components. These findings indicate that 17 beta-estradiol is the key compound of the conjugated estrogen mixture effective on bleeding time shortening and that the effect of estrogens on primary hemostasis is mediated by a receptor mechanism.