We have investigated the effects of long-term estrogen withdrawal or tamoxifen therapy of MCF-7 human breast cancer cells growing in the athymic nude mouse to clarify mechanisms by which endocrine therapy inhibits tumor growth. Estrogen withdrawal with or without tamoxifen inhibited MCF-7 tumor growth, but did not cause significant regression, even after 4 months of treatment. Serial histologic studies of treated tumors revealed a reduction in mitotic rate but no significant gross or ultrastructural cytopathic changes. Treated tumors did show a modest increase in stromal fibrosis as well as occasional cytoplasmic or nuclear vacuolization, perhaps indicating early cytopathic effects. Cell viability was confirmed by cloning tumor cells in soft agar; cloning efficiency in treated tumors was similar to that in controls. Tumor fragments from treated mice were also viable and formed tumors when transplanted into estrogen-supplemented but not estrogen-deprived mice indicating continued hormone dependence. When estrogen-deprived or tamoxifen-treated mice were replenished with estrogen, cell proliferation was reactivated and tumor growth resumed. After 3-4 months of endocrine therapy, tumors began to regrow despite continued treatment suggesting the conversion to hormone independence. These studies suggest that in this model system, estrogen withdrawal and antiestrogen therapy work primarily by cytostatic rather than cytocidal mechanisms.