This phase II trial evaluated the clinical role of interferon (IFN) in overcoming tamoxifen (TAM) resistance in breast cancer. Twenty women and 1 man received recombinant alpha interferon (5 million units per meter squared intramuscularly, 5 times per week) plus TAM (10 mg orally, twice daily) for the treatment of metastatic breast cancer, either after failing tamoxifen therapy or as frontline hormonal therapy. Of the 9 evaluable patients with disease progression after an objective response to TAM, there were no partial or complete responses with the addition of IFN. Ten evaluable patients received TAM plus IFN as frontline hormonal therapy with 2 complete and 3 partial responses for an overall response rate (RR) of 50% (95% confidence interval = 19-81), a 71% RR for ER-positive patients (95% confidence interval = 29-96) and no responses in ER-unknown patients. Sixteen patients required dose reductions of IFN and 8 patients discontinued therapy due to toxicity. It is unlikely that the RR for TAM plus IFN is greater that than seen with TAM alone, or that the addition of IFN to TAM therapy can overcome clinical TAM resistance.