Pneumonic plague is the most deadly form of infection caused by Yersinia pestis and can progress extremely fast. However, our understanding on the host transcriptomic response to pneumonic plague is insufficient. Here, we used RNA-sequencing technology to analyze transcriptomic responses in mice infected with fully virulent strain 201 or EV76, a live attenuated vaccine strain lacking the pigmentation locus. Approximately 600 differentially expressed genes (DEGs) were detected in lungs from both 201- and EV76-infected mice at 12 hours post-infection (hpi). DEGs in lungs of 201-infected mice exceeded 2,000 at 48 hpi, accompanied by sustained large numbers of DEGs in the liver and spleen; however, limited DEGs were detected in those organs of EV-infected mice. Remarkably, DEGs in lungs were significantly enriched in critical immune responses pathways in EV76-infected but not 201-infected mice, including antigen processing and presentation, T cell receptor signaling among others. Pathological and bacterial load analyses confirmed the rapid systemic dissemination of 201-infection and the confined EV76-infection in lungs. Our results demonstrate that fully virulent Y. pestis strongly inhibits both the innate and adaptive immune responses that are substantially stimulated in a self-limited infection, which update our holistic views on the transcriptomic response to pneumonic plague. Overall design: We used RNA-sequencing technology to analyze transcriptomic responses in lungs, spleen and liver of mice infected with fully virulent strain 201 or EV76 at 12, 48 and 72 hpi.