Ovarian cancer is one of the most common and deadly types of cancer in women and effective treatments are lacking. Patients with the most prevalent form of the disease ― high-grade serous cancers (HGSC) ― mostly present with advanced disease. The standard of care is debulking surgery and chemotherapy to which a majority develop resistance. Taken together these data highlight the need for new insights into the development and pathogenesis of these cancers in order to develop new treatments. Previously, we discovered interferon-ε (IFNε) as a novel cytokine that is constitutively expressed and hormonally regulated by epithelial cells in the female reproductive tract (FRT) and drives protection against common sexually transmitted infections [Fung et al Science 2013 ]. Here, we report that IFNε also shapes a unique anti-tumour response in the FRT that is specifically tailored to the tissue. We used syngeneic mouse models of ovarian cancer together with genomic analysis of large cohorts of women with HGSC to demonstrate that loss of IFNε results in increased tumourigenesis, poor disease prognosis and reduced survival. In mouse models of developing, established and advanced ovarian cancer, treatment with recombinant human IFNε inhibited peritoneal tumourigenesis by two main mechanisms. First, IFNε directly inhibited the proliferation of tumour cells and induced tumour cell apoptosis. Second, IFNε activated peritoneum anti-tumour immune cells including CD8 T cells and NK cells and modulated the expression of immune checkpoint molecules. Comparative studies showed that IFNε was a more effective inhibitor of ovarian cancer than IFNβ. Thus, we demonstrate that IFNε is a novel, intrinsic, tissue-specific tumour suppressor in the FRT and potential treatment for HGSC, whose repertoire of activities may be suitable for mono-, adjuvant or combination therapy with immune- or chemotherapy.