Gamma-knife radiosurgery is one of the only means of treating otherwise inoperable intracranial neoplasia. At present the mechanism by which single-dose γ-radiation reduces tumor bulk is unknown. Using the human mammary cell line MCF-7 to represent a metastatic tumor often treated by γ-knife radiosurgery, we show here that γ-radiation provided by the γ knife dose dependency reduced growth and a component of this response was the induction of apoptotic cell death. Since we have shown previously that, for estrogen receptor-containing pituitary tumor cells, the pure antiestrogen, ZM 182780, modulates cell survival, further experiments were performed in which γ-irradiation was combined with ZM 182780 or the more familiar antiestrogen, tamoxifen. Our data demonstrate that although tamoxifen was as effective as ZM 182780 at blocking the transcriptional activity of the estrogen receptor, it was the pure antiestrogen that significantly enhanced apoptosis induced by γ-irradiation. These results on combining γ-irradiation with a pure antiestrogen offer a new therapeutic paradigm by which the effectiveness of γ-knife treatment could be enhanced by agents that modulate the apoptotic pathway.