Hesperidin is a flavonone glycoside found abundantly in citrus fruits that reportedly possesses anti-inflammatory, anticancer, and immune effects. Irradiation has been widely used for both diagnostic and therapeutic purposes, but it has the side effect of damaging normal cells and thereby inducing inflammation. This study was performed to investigate the effect of hesperidin on immune reactivity and nutritional status in mice with irradiation-induced inflammation. Two different concentrations (50 mg/kg and 200 mg/kg of body weight) of hesperidin were orally administered for 6 weeks to mice with or without 15-Gy irradiation treatment starting 2 weeks before irradiation. Splenocyte proliferation on Day 10 after irradiation was enhanced by supplementation with hesperidin at 50 mg/kg of body weight compared with that of the control group without irradiation on Day 30 after irradiation. The percentages of CD4(+) and CD8(+) lymphocytes in the 50 mg/kg of body weight hesperidin group tended to increase compared with the normal group. The concentration of serum cytokines (interleukin-1β, interleukin-6, and tumor necrosis factor-α) decreased in the radiation group treated with hesperidin at 50 and 200 mg/kg of body weight compared with the control group on Day 10 after irradiation. Irradiated mice fed 50 mg/kg of body weight hesperidin had significantly higher levels of total protein and albumin compared with the other groups 30 days after irradiation. In conclusion, this study suggests that hesperidin may enhance immunocompetence, have beneficial effects on nutritional status, and decrease irradiation-induced inflammation in mice.