The oncolytic rodent protoparvoviruses (PV) MVMp and H-1PV are under investigation for their immunotherapeutic potential. The presence of interferon-β (IFN-β), a type-I IFN cytokine, and the activation of IFN-β signaling pathways in the tumor microenvironment are considered instrumental for favorable long-term effects of several types of cancer treatments. PV-induced IFN-β production was shown to be significant yet weak in infected non-malignant cells, including immune cells and fibroblasts, but could not be detected in infected neoplastic cells, even though these cells were intrinsically competent in this process. The evasion of PV-infected tumor cells from IFN-β production may limit the immunostimulatory and oncosuppressive potential of these viruses. This prompted us to further characterize the molecular mechanisms underlying PV modulation of IFN-β expression in infected neoplastic cells. PV induction of IFN-β was found among others (i) to be independent of various known pattern recognition receptor pathways, (ii) to be initiated (NFκB and IRF3 nuclear translocation) in both normal and tumor cells concomitantly with the nuclear accumulation of PV-encoded dsRNA molecules, but (iii) to go to completion (IFN-β production and release) only in normal cells, while IFN-β mRNA transcription was blocked in transformed cells. This intriguing PV suppression of a late step in IFN-β induction in infected tumor cells leads us to speculate that this inhibition may be prevented through viral genome manipulation; this could potentially restore PV-initiated production of immunogenic IFN-β, and/or be taken advantage of in treatments combining PV with IFN-β-sensitive oncolytic agents.