Since experimental studies have shown that tumour necrosis factor-α (TNF-α) has potent anti-tumour activity that can be potentiated with cytokines, we tested the efficacy of TNF-α with interferon-γ (IFN-γ) on different human breast cancer cell lines, particularly comparing hormone-dependent and -independent phenotypes. TNF-α inhibited the growth of hormone-dependent human MCF-7, ZR-75-1 and T47-D breast cancer cells with a half maximal concentration of 0.25 nM. In contrast, the growth of hormone-independent cells MDA-MB-231 and HS578T was not affected by TNF-α alone, but a synergistic inhibition was observed when using IFN-γ and TNF-α together. The mRNA for the proto-oncogene C-MYC, as an intracellular indicator of cell activation, was significantly increased in MCF-7 cells in the presence of TNF-α. In MDA-MB-231 cells this mRNA was increased only in the presence of both TNF-α and IFN-γ, without a change in the number of surface TNF receptors. These findings indicate that TNF-α treatment in combination with IFN-γ may provide a successful approach to overcome the cellular heterogeneity of advanced breast tumours.