A difficulty in studying hemorrhagic arenavirus pathogenesis is a lack of animal models that recapitulate human disease and which can be manipulated at BSL-3 or lower. Pirital virus (PIRV), a South American arenavirus hosted by Alston’s cotton rats (Sigmodon alstoni), has not been shown to cause disease in humans and is considered a BSL-3 agent. Infection of Syrian golden hamsters (Mesocricetus auratus) causes a disease that shares many features of the South American hemorrhagic fevers and Lassa fever. Significantly, neurological manifestations occur, a feature commonly found in Argentine hemorrhagic fever and which is absent in most other models of arenavirus disease. We examined the pathogenesis of PIRV infection by clinical and molecular methods, with a focus on gene expression of the antiviral type I interferon response using RNA-Seq. More than 3,000 genes were differentially expressed in the livers of infected hamsters, of which 86 are involved with antiviral responses. Several of these genes participate in apoptosis and autophagy, which may suggest a mechanism of pathogenesis observed in damaged livers.