Infection with porcine reproductive and respiratory syndrome virus (PRRSV) results in a weak antiviral immune response that leads to a persistent infection in a subset of pigs. We investigated the intensity and timing of the early cytokine responses to PRRSV infection to determine their utility as a predictor of persistence. As part of the “Big Pig” project, we evaluated cytokine gene expression in lymphoid tissues collected from pigs for up 202 days post-infection (dpi); serum samples were collected biweekly. Cytokine mRNA levels were compared between pigs that cleared the viral infection from serum and tissues (non-persistent [NP] pigs) to those of persistent (P) pigs, that had viral RNA in their serum for up to 126 dpi. The gene expression studies in the tracheobronchial lymph nodes (TBLN) of all the pigs showed upregulation of interferon-γ (IFN-γ)-associated T-helper 1 (Th-1) markers from 14–84 dpi, and of T-regulatory interleukin-10 (IL-10), but no upregulation of innate markers (IFN-A, IL-1B, and IL-8). At later time points (>112 dpi) these genes were no longer differentially expressed and thus were uninformative for persistence studies. Statistical analyses of serum cytokine levels indicated that innate cytokine (IL-1β and IL-8) levels were upregulated early after infection. Interestingly, serum IL-8 levels in NP pigs were significantly higher than in P pigs at 14 dpi. When analyzed together, variations in all three of the serum cytokines tested (IL-8, IL-1β, and IFN-γ) was significantly correlated with virus level, accounting for ∼84% of the variations observed. These results indicate that while each cytokine individually has minor effects on the length of virus replication, the combination of cytokine activities should be considered when understanding the role of immunity in persistence.