Lungs are highly vascularised organs directly exposed to atmospheric oxygen. Consequently, they are an important source of reactive species that seem to be involved in local defense against pathogens. With age, increased production of free radicals, together with a reduced antioxidant defense activity, may surpass the antioxidative capability of lungs, leading to lung damage and increasing susceptibility to other pathologies. Xanthohumol, the major prenylated chalcone found in hops, has been shown to present anti-inflammatory and antioxidant properties in several organs, including liver, brain, and at the level of the reproductive system. Its effect on the aging lung has yet to be elucidated. For this reason, the aim of the present study was to evaluate the possible anti-inflammatory role of xanthohumol on a model of male senescence-accelerated prone mice (SAMP8). Young and old animals, aged 2 and 10 months respectively, were maintained under a 12:12 h light-dark cycle in an environmentally-controlled room and fed ad libitum. They were divided into 4 experimental groups: Young non-treated, old non-treated, old treated with 1 mg/kg/day xanthohumol, and old treated with 5 mg/kg/day xanthohumol. Young and old non-treated male senescence-accelerated resistant mice (SAMR1) were used as controls. Xanthohumol was dissolved in ethanol and added to the drinking water. Only ethanol was administered to the water of non-treated animals. After 30 days of treatment, animals were sacrificed and lungs were collected and immediately frozen in liquid nitrogen. mRNA expression of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), nuclear factor NF-kappa-B p100 subunit (NFκB2), and heme oxygenase 1 (HO1) was measured by means of RT-PCR using the SYBR Green PCR Master Mix (Applied Biosystems, Warrington, UK) and 300 nM concentrations of specific primers. For the normalization of cDNA loading in the PCR reaction, the amplification of 18S rRNA for every sample was used. Relative changes in gene expression were calculated using the 2-ddCt method. Mean values were analyzed by ANOVA. Compared to the young animals, old non-treated SAMP8 mice presented significantly elevated (P<0.05) mRNA levels of TNF-α, IL-1β, NFκB2, and HO1. SAMR1 mice showed significantly decreased (P<0.05) mRNA levels of these pro-inflammatory markers in comparison with the old non-treated SAMP8 group. Treatment with xanthohumol was able to decrease significantly (P<0.05) the age-induced elevation at any of the doses administered. Supplementing the diet with foodstuffs containing xanthohumol may be used as a potential tool for counteracting inflammation and oxidative stress in the aging lung.