Chronic hyperbaric oxygen (HBO) therapy significantly attenuates atherosclerosis in New Zealand white rabbits as well as the apoE knockout (KO) mice, independent of plasma lipid concentrations and lipoprotein profiles. Because atherosclerosis has many features of a chronic inflammatory disease, in which both cell-mediated and humoral immune responses participate, we examined the effect of HBO treatment on various aspects of the immune response. We now demonstrate that in apoE KO mice, HBO treatment significantly reduces the circulating levels of antibodies to (MDA)LDL, both in the IgG and IgM class, as well as the delayed-type hypersensitivity (DTH) response to oxLDL challenge. Furthermore, HBO treatment results in a profound attenuation in the production of pro-inflammatory cytokines in response to an inflammatory stimulus (LPS), which is accompanied by a marked increase in the constitutive production of the anti-inflammatory cytokine IL-10 by spleen cells, independent of antigen specificity, as indicated by polyclonal activation of T cells. Our results demonstrate that HBO treatment results in the dampening of T and B cell-mediated responses to oxLDL or inflammatory stimuli.