The genusAnaplasma(Rickettsiales: Anaplasmataceae) includes obligate tick-transmitted intracellular organisms,Anaplasma phagocytophilumandAnaplasma marginalethat multiply in both vertebrate and tick host cells. Recently, we showed thatA. marginaleaffects the expression of tick genes that are involved in tick survival and pathogen infection and multiplication. However, the gene expression profile inA. phagocytophilum-infected tick cells is currently poorly characterized. The objectives of this study were to characterize tick gene expression profile inIxodes scapularisticks and cultured ISE6 cells in response to infection withA. phagocypthilumand to compare tick gene expression responses inA. phagocytophilum- andA. marginale-infected tick cells by microarray and real-time RT-PCR analyses. The results of these studies demonstrated modulation of tick gene expression byA. phagocytophilumand provided evidence of different gene expression responses in tick cells infected withA. phagocytophilumandA. marginale. These differences inAnaplasma-tick interactions may reflect differences in pathogen life cycle in the tick cells.