Type I interferons (IFNs) play a central role not only in innate immunity against viral infection, but also in the antitumour response. Apart from indirect immune-modulatory and anti-angiogenic effects, they have direct impact on cell proliferation. Particularly for cancer arising in the context of chronic inflammation, constant exposure to IFNs may constitute a strong selective pressure during tumour evolution. Expansion of neoplastic subclones or -populations that developed resistance to the antiproliferative effects of IFNs might constitute an important contribution to immunoediting of the cancer cells leading to more aggressive and metastasising disease. Experimental evidence for this development of IFN-insensitivity has been scarce and its molecular mechanism is unclear. In this study we demonstrate that prolonged (six weeks) exposure of cells to IFN-β in vitro reduces their sensitivity to its antiproliferative effects, and that this phenotype was stable for up to four weeks. Furthermore, we observed substantial differences in cellular sensitivity to growth inhibition by IFN-β in a panel of ten different liver cancer cell lines of varying malignity. IFN-resistance was most prominent in a pair of highly dedifferentiated cell lines, and least in cells from well-differentiated tumours, fostering the hypothesis of IFN-driven immunoediting in advanced cancers. In both settings, long-term IFN selection in vitro as well as in dedifferentiated tumour cell lines, we found IFNAR expression to be substantially reduced, suggesting the receptor complex, in particular IFNAR2, to be a sensitive target amenable to immunoediting. Beyond new insights into possible molecular processes in tumour evolution, these findings might prove valuable for the development of biomarkers allowing to stratify tumours for their sensitivity to IFN treatment in the context of patient tailored therapies.