The influence of a selenium deficient diet in mice and rats has been studied on glutathione peroxidase (GSH-Px) and secretory activities of peritoneal macrophages, mitogenesis of spleen cells and adjuvant arthritis. Macrophage GSH-Px activity was significantly reduced from 9 weeks on the selenium deficient diet. This reduction was associated with enhanced macrophage H2O2 release on zymosan stimulation after 12 weeks on the diet, a similar trend in chemiluminescence and reduced mitogenesis of spleen cell cultures to T and B cell mitogens after 8 weeks on the diet. Macrophage beta-glucuronidase release was not significantly altered. Phorbol myristic acetate induced macrophage H2O2 generation was reduced by selenium deficiency, possibly due to increased cellular damage. Adjuvant arthritis of rats was significantly enhanced after 6 and 12 weeks on the selenium deficient diet. The enhanced release of H2O2 by macrophages after zymosan stimulation can be directly attributable to loss of GSH-Px activity leading to reduced peroxide breakdown. Peroxide-mediated cell injury would also account for the reduction in lymphocyte mitogenesis and enhancement of adjuvant arthritis. These data provide support for a role of selenium in immune and inflammatory responses.