Hochuekkito (HET), a Kampo medicine, is used to treat post-operative and post-illness general malaise and decreased motivation. HET is known to regulate immunity and inflammation. However, the mechanism underlying the anti-anxiety effect of HET is unknown. In this study, we revealed the effect of HET on lipopolysaccharide (LPS) -induced anxiety-like behavior　and examined the mechanism underlying LPS induced anxiety-like behaviors. Following the administration of LPS (300 µg/kg, i.p.), mice demonstrated inflammation-induced anxiety-like behaviors in hole-board and light-dark box tests. Systemic administration of LPS increased the serum levels of interleukin-6. Repeated administration of HET (1.0 g/kg, p.o.) once a day for 2 weeks before LPS treatment ameliorated anxiety-like behavior and reduced LPS-induced serum levels of interleukin-6 in 5 h after LPS treatment. Additionally, HET decreased LPS-induced secretion of interleukin-6 in human macrophage cell line (THP-1) and mouse macrophage cell line (RAW264.7) as in mouse models. Therefore, our findings suggest that HET may be useful in treating inflammation-induced anxiety-like behavior.