Porcine reproductive and respiratory syndrome virus (PRRSV) continues to be an economically important infectious disease of swine. Mechanisms governing activation of the innate immune response to PRRSV remain to be elucidated. Virulence differences observed between PRRSV isolates have been attributed to replication ability in vivo, though immunogenic differences likely contribute to virulence also. The current study utilized a single PRRSV isolate given at two different challenge doses to investigate the effect of viral replication and load on immune responses, including type I interferon activation. Body temperature, viral load, antibody levels, cellular infiltration into pulmonary tissue, and the interferon response were measured in animals receiving either a low (10(2) CCID(50)) or high (10(6) CCID(50)) dose of inoculum to understand the role of challenge dose in acute immune responses. Initial PRRSV dose did not correlate with serum levels of PRRSV vRNA or antibody titers during the acute stage of infection (days 2-12 PI), but did have an effect on the immune response and mortality. Type I interferon responses, measured by transcriptional changes in IFN-beta, IFN-alpha, Mx, and PKR, were uniquely different when assessed relative to viral dose or cell type, but no overall trend existed to discern responses based on challenge dose. Serum IFN-gamma levels correlated with serum viral RNA load at day 19 PI. Overall, between days 2 and 12 PI, serum vRNA load was not significantly different between pigs challenged with a low or high dose of PRRSV. Animals receiving high-dose inoculum were viremic longer and eventually succumbed to respiratory disease. IFN-gamma may play a role in PRRSV pathogenesis, as serum levels increased significantly in pigs challenged with the high dose of PRRSV.