Background: Malignant catarrhal fever is a lymphoproliferative disease of cattle and other ungulates caused by infection with gamma-herpesviruses of the genus Macavirus. These viruses do not establish a productive infection but instead replicate in a cell-associated fashion in T lymphocytes, leading to systemic immune dysregulation and a generally fatal outcome. Despite significant progress in understanding the pathology of this disease, its pathogenesis remains unclear. Methods/Findings: To identify genes and pathways affected in clinical MCF, sixteen bovine GeneCHIP microarrays, representing over 24000 transcripts, were used to assay RNA from kidney and lymph node of four MCF-affected and four control steers. Over 3000 genes in lymph node and over 1700 genes in kidney showed significant changes in gene expression, while expression of over 500 genes was altered in both tissues. Pathway and annotation analysis of the microarray data showed that immune response and inflammatory genes were up-regulated in the kidney while proliferation-associated transcripts were increased in the lymph node. The genes that showed the largest expression rises in both diseased tissues included cytotoxic enzymes, chemokines and T cell markers. Conclusions/Significance: These data are consistent with disease-induced stimulation of cytotoxic T cell recruitment and activation in peripheral tissues containing virus-infected cells. However it remains unclear whether the tissue damage in MCF lesions is due entirely to the activity of infected cells or whether uninfected T cells, recruited and activated at lesions sites through the action of infected cells, contribute to the systemic effects of MCF.