Elemental mercury (Hg(0)) is a hazardous metal with significant human exposure through diverse sources. In this study, the role of salicylic acid (SA) was assessed against Hg(0)-induced injury in mice, with the aim of screening alternative clinical drugs to prevent or treat Hg(0) poisoning. An exposure to Hg(0) (1.0 mg/m(3) in a glass box) for 2 h per day for successive 15 d significantly increased Hg accumulation in mouse brain and lung, inhibited the animal growth and altered the neurobehavior such as impairing the spatial learning and memory in the Barnes maze test. However, although oral SA (5.5 mg/kg body weight) during the Hg(0) exposure did not reduce the Hg levels in these organs, it effectively counteracted the Hg(0)-induced growth inhibition, and improved the behavioral performance, accompanied by a series of ameliorations in the antioxidative defense and anti-inflammatory response. For instance, when compared with control, Hg(0)-inhaled animals had significant decreases in the activities of superoxide dismutase and peroxidase, and in the levels of reduced form of glutathione and the ratio to its oxidized form, concomitantly with a high accumulation of hydrogen peroxide and malondialdehyde in the brain and lung. However, these values in Hg(0) + SA-exposed animals were comparable with the basal levels in control. Likewise, interleukin-6 in the brain and lung of Hg(0)-exposed animals were dramatically elevated, whereas it was maintained to the basal level in Hg(0) + SA-exposed animals. These data suggested that application of SA could protect mice against Hg(0)-induced injury.