Interferon-ε (IFNε) is a unique type I IFN that is constitutively expressed by epithelial cells in the female reproductive tract (FRT), where it shows antimicrobial activities. Here, Marks et al. report that IFNε also has anti-tumour functions in the FRT. They found that IFNε is constitutively expressed by epithelial cells in the fallopian tubes of healthy women, but significantly suppressed in low-grade and high-grade serous ovarian cancers. In mouse models of ovarian cancer, increased metastasis to the peritoneum occurred in IFNε-deficient mice, whereas treatment of wild-type mice with IFNε reduced peritoneal metastases in a dose-dependent manner. Treatment with IFNε also suppressed the spread of established ovarian cancers in mice. The authors identified both direct and indirect modes of action — IFNε had pro-apoptotic and anti-proliferative effects on tumour cells, and promoted the activation and cytotoxic functions of T cells and natural killer cells in the peritoneum while suppressing immunosuppressive populations. Notably, IFNε therapy could still suppress the spread of ovarian tumours deficient in IFN receptor signalling. Thus, IFNε therapy could be effective against tumours that have developed resistance to IFN stimulation.