Neurokinin (NK) signaling is involved in various inflammatory processes. A common manifestation of systemic inflammation is fever, which is usually induced in animal models with the administration of bacterial lipopolysaccharide (LPS). A role for the NK1 receptor was shown in LPS-induced fever, but the underlying mechanisms of how the NK1 receptor contributes to febrile response, especially in the early phase, have remained unknown. We administered LPS (120 µg/kg, intraperitoneally) to mice with the gene, i.e., the gene encoding the NK1 receptor, either present ( ) or absent ( ) and measured their thermoregulatory responses, serum cytokine levels, tissue cyclooxygenase-2 (COX-2) expression, and prostaglandin (PG) E concentration. We found that the LPS-induced febrile response was attenuated in compared to their littermates starting from 40 min postinfusion. The febrigenic effect of intracerebroventricularly administered PGE was not suppressed in the mice. Serum concentration of pyrogenic cytokines did not differ between and at 40 min post-LPS infusion. Administration of LPS resulted in amplification of COX-2 mRNA expression in the lungs, liver, and brain of the mice, which was statistically indistinguishable between the genotypes. In contrast, the LPS-induced augmentation of COX-2 protein expression was attenuated in the lungs and tended to be suppressed in the liver of mice compared with mice. The mice responded to LPS with a significant surge of PGE production in the lungs, whereas mice did not. In conclusion, the NK1 receptor is necessary for normal fever genesis. Our results suggest that the NK1 receptor contributes to the early phase of LPS-induced fever by enhancing COX-2 protein expression in the periphery. These findings advance the understanding of the crosstalk between NK signaling and the "cytokine-COX-2-prostaglandin E" axis in systemic inflammation, thereby open up the possibilities for new therapeutic approaches.