This study explored the activity of natural interferon-alpha (nIFN-a) in regulating cell growth of 6 breast-cancer cell lines. The anti-proliferative effect of the combination nIFN-a and tamoxifen (TAM) or medroxyprogesterone acetate (MPA) in CG-5 estrogen-sensitive mammary cancer cells was investigated, and the ability of nIFN-a to restore hormonesensitivity in the MPA-resistant MCF-7 SK sub-line was examined. nIFN-a, at concentrations ranging from 10 to 1000 IU/ml, inhibited cell proliferation of all cell lines tested after 3 and 6 days of treatment. In particular, the highest concentration of the drug used was equally effective in hormonesensitive and in hormone-insensitive cells. A 6-day pretreatment of CG-5 cells with nIFN-a, at the above-mentioned doses, sensitized them to the growth-inhibiting activity of subsequent exposure to 10 27 M TAM or MPA, which resulted in a synergistic effect, and could be explained on the basis of the observed enhancement of estrogen and progesterone receptors due to IFN activity. Conversely, the simultaneous drug combination did not modify the response to the hormone in CG-5 cells. Pre-treatment with nIFN-a (from 10 to 1000 IU/ml) restored MPA sensitivity in the MCF-7 SK sub-line, but no modulation of progesterone receptors was seen in this model. The hormone-sensitivity of the parental cell line was not substantially affected by pre-exposure to nIFN-a. These data indicate that nIFN-a may be potentially useful in enhancing the clinical effectiveness of TAM and MPA and in overcoming hormone resistance.