Interferon-α (IFN-α) is a cytokine that is effective in the treatment of a variety of cancers, including non-melanoma skin cancers. The biologic responses of cells to IFN-α are pleiotropic and include growth suppression and immunomodulation. The potential direct effects of IFN-α on tumor cell populations are incompletely characterized. Our findings indicate that IFN-α can directly induce apoptosis (programmed cell death) in sensitive squamous cell skin cancer cell lines. Cell lines resistant to the cytotoxic effects of IFN-α showed no evidence of apoptosis induction. Transfection of IFN-α-sensitive cell lines with a bcl-2 expression vector conferred partial resistance to cell death induction by IFN-α Our results indicate that the clinical efficacy of IFN-α may, in part, be related to the ability of this cytokine to induce apoptosis. © 1995 Wiley-Liss, Inc.