Yersinia pestis, the causative agent of plague, is known to develop strategies to overcome the host immune mechanisms and survive in the host. The molecular changes induced by Y. pestis in the host are not well delineated. Here, we examined the early events triggered after the intracellular infection of Y. pestis in human monocytes and lymphocytes by analyzing the host transcriptional profiles using cDNA arrays. We found that sets of genes that, especially at early time periods, were highly upregulated in monocytes alone when compared with a mixed culture of lymphocytes and monocytes. Gene expression responses revealed genes coding for cytokines, chemokines, transcription factors, inflammatory and apoptosis-related genes. Protein levels were measured, and real-time polymerase chain reaction was used to validate the microarray results. Our data suggest that intracellular infection of human monocytes with Y. pestis results in a strong inflammatory response at early time periods and a downregulation of genes such as thromobomodulin, which may play a role in coagulation, resulting in disseminated intravascular coagulation, a primary cause of death in plague infected hosts. We provide evidence that genomic analysis can provide a solid foundation to mechanistic insights to explain some of the symptoms induced by Y. pestis.