Marek's disease is a viral neoplastic disease of chickens caused by Marek's disease virus (MDV). Gene expression patterns have been investigated at different MDV infection stages, but there is limited research about the late tumor transformation phase. In this experiment, 44K Agilent chicken genome-wide expression microarrays were used to profile differential expression in tumorous spleens (TS) from severely morbid chickens and apparently normal spleens from survivors (SS) after MDV infection and expression in noninfected spleens (NS) from controls. There were 4,317 differentially expressed (DE) genes in TS versus NS. However, no DE genes were detected in SS versus NS, suggesting that maintenance of, or return to, homeostasis of gene activity in survivor spleens. Downregulated genes in tumorous spleens mainly enriched in the cytokine-cytokine receptor interaction pathway, and commonly investigated genes in Marek's disease study, IL6, IL18, IFNA, and IFNG were nondifferentially expressed, which indicates host inflammatory response was impaired. The IL10 and TNFRSF8 genes were upregulated in tumorous spleens. We speculated that IL10 might be exploited by MDV to escape from host immune surveillance, as reported for Epstein-Barr virus, which stimulated T cells secreting IL10 to subvert immune response. Previous study reported that transcription from TNFRSF8 promoter could be enhanced by MDV oncogene Meq. In this study, the increased expression of TNFRSF8 indicated interaction between MDV and TNFRSF8, which might facilitate pathogenesis and tumor transformation. The expression of many members in IGF system was changed in tumorous compared with noninfected spleens. The downregulation of IGFBP7 was considered to be associated with MD lymphoma transformation. Gene expression change of multiple regulatory pathways indicated their involvements in facilitating tumor transformation.