This study describes the use of adult rats as a model to determine whether chronic estrogen treatment irreversibly alters the capacity of Sertoli cells to secrete androgen binding protein (ABP). Twenty-five adult rats were implanted with silastic tubing containing 17 beta-estradiol. After 1 month of estradiol the epididymides had regressed to 47 per cent of the weight of the epididymides in a control group. The amount of ABP in control epididymides was 9.9 fmol./mg. protein, whereas no ABP was detectable in those from rats treated with estradiol for 1 month. Serum testosterone levels had been depressed by 90 per cent. Estradiol treatment for 8 months resulted in a 60 per cent lower body weight and a 91 per cent decrease in testicular weight compared to control animals. During this period the epididymides regressed significantly. When Sertoli cells were cultured from the testes of the estradiol implanted rats, in spite of the dramatic changes which had occurred in the testes, within 4 days the cultured cells synthesized ABP in response to FSH and testosterone. Furthermore, the direct addition of estrogen at a concentration of 200 ng./ml. to rat Sertoli cell cultures failed to depress ABP below control levels. Thus, although estradiol depresses ABP synthesis in vivo, probably through its depression of both gonadotrophin secretion and testosterone biosynthesis, it has no direct effect on the Sertoli cells, and its long-term inhibition of ABP synthesis by an indirect mechanism is reversible.