The host susceptibility to endotoxin (lipopolysaccharide, LPS), production of interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor-alpha (TNF-alpha) or phagocytosis in resident peritoneal macrophages were examined in iron-deficient and iron-loaded mice. Four groups of weanling male CD-1 mice were fed diet containing 7, 120, 5000 or 8000 ppm iron for 7 w. Body weight gain or hematocrit was not affected by iron consumption except for a lower weight gain in mice fed the 8000f1p4 iron diet. Iron-deficient and loaded diets produced a marked decrease and increase in liver iron concentration, respectively (P< 0.05). When challenged with an ip lethal dose of LPS, mortality was enhanced in iron-deficient and loaded mice (P= 0.035). The production of TNF-alpha and IL-1 alpha was assessed in the peritoneal macrophages stimulated by LPS in vitro. The production of IL-1 alpha and TNF-alpha was not altered in macrophages from iron-deficient mice. In contrast, macrophages from the 2 iron-loaded groups of mice produced more TNF-alpha (150% of control) without altering IL-1 alpha production. However, the total peritoneal leukocyte cell yield was not different among the treatment groups. Phagocytosis in the peritoneal macrophages determined by in vitro uptake of yeast cells was lower in the iron-deficient or loaded mice. This study indicates that iron deficiency and overload enhance LPS toxicity and impair phagocytosis, whereas excess iron also increases TNF-alpha production by macrophages.