Viral respiratory diseases are problematic in swine industry. Among viruses, porcine reproductive and respiratory syndrome virus (PRRSV) and swine influenza virus (SIV), alone or in combination, are two main known contributors to respiratory infectious diseases. In the field, single viral infection is not frequent and most of the time association of infectious agents is encountered. So far most of the studies focused on single infectious agents ignoring the interactions existing between various pathogens (additive effects, synergism or antagonism) and their consequences for prophylactic treatments. In the current study we used a modified newborn pig trachea (NPTr) cell line expressing CD163, the receptor of PRRSV virus. Using this epithelial cell line allowing co-infections we assessed the impact of single infections compared to co-infections using specific strains and focusing on viral replication and the induction of cellular response, its characterization, and its regulation. One virus could influence the replication of the other, especially when the first virus inoculated to the cell was PRRSV. Regarding the triggering of cellular response the outcome is complex and target dependent. In some cases, co-infection did not lead to any synergism or additive effects while in other situations we observed a clear antagonism. Thus, obvious synergisms between the two viruses were not reported in any situations. In conclusions, using cells that can be infected with both PRRSV and SIV, we did not observe any synergism in the cellular response developed against viruses. On the contrary it appeared that the first virus was negatively influencing the replication of the second and the associated cellular response. Further studies are required to fully decipher the complex interactions occurring between the two viruses in their host.