Technical Abstract: Porcine reproductive and respiratory syndrome (PRRS) is one of the most devastating and costly diseases to the swine industry world-wide. Overall, the adaptive immune response to PRRS virus (PRRSV) is weak and results in delayed elimination of virus from the host and inferior vaccine protection. PRRSV has been shown to induce a meager interferon (IFN)-alpha response, and in a previous study by our group, pigs that were injected with a nonreplicating human adenovirus type 5 vector expressing porcine interferon-alpha (Ad5-pIFN-alpha) and then challenged one day later with PRRSV had delayed viral replication and diminished disease severity. In this study, we followed the immune response in swine given Ad5-pIFN-alpha and challenged with PRRSV simultaneously. Not only was viremia delayed, but there was a decrease in viral load in the sera of pigs administered the Ad5-pIFN-alpha. Although seroconversion was slightly delayed in pigs receiving IFN-alpha, probably due to the delay in viremia, little difference was seen in the overall or neutralizing antibody response. However, there was an increase in virus-specific IFN-gamma secreting cells detected in the pigs receiving IFN-alpha, as well as an altered cytokine profile in the lung 14 days post infection, indicating that the presence of IFN-alpha at the time of infection can alter the innate and adaptive immune response to PRRSV.