ASFV causes an important disease of domestic swine and wild boar. Currently no vaccine is available, highlighting the necessity to understand ASFV modulation of innate immune responses in natural host cells. With this aim, macrophage cultures enriched in SWC9 and CD163 differentiation markers were infected in parallel with high virulent ASFV/L60 and low virulent ASFV/NHV, the latter lacking MGF 360 and 505/530 genes associated with type I interferon (IFN I) control. IFN I production and signaling were studied after completion of the viral cycles. None of the viruses increased IFN I production in host cells, and accordingly, didn't cause activation of the central mediator of the pathway IRF3. However, upon stimulation by poly:IC treatment during infections, L60 and NHV similarly inhibited IFN I production. This didn't seem to depend on IRF3 modulation since its activation levels were not significantly decreased in L60 infection and were even increased in NHV's, in comparison to stimulated mock infections. The infections didn't evidently activate JAK-STAT pathway mediators STAT1 and STAT2, but did increase expression of interferon stimulated genes (ISGs), to higher levels in NHV than L60 infection. Interestingly, in presence of IFN-alpha, L60 but not NHV was able to decrease significantly the expression of some of the ISGs tested. Overall, both L60 and NHV were able to inhibit IFN I production in macrophages, through a mechanism not dependent on IRF3 modulation. The high virulent isolate showed however a more effective control of the downstream ISGs expression pathway.