Because protein‐malnourished or endotoxemic patients are at an increased risk of developing nosocomial infections, this study was performed to investigate the effects of protein malnutrition and endotoxemia, alone and in combination, on systemic and intestinal immunity. Protein malnutrition was created by feeding the animals a solid diet containing 0.03% protein. Subgroups of these protein‐malnourished mice were killed after being challenged with saline or endotoxin on days 0, 7, 14, or 21. At death, the animals were weighed, tissues were harvested for histologic analysis (ileum, mesenteric lymph node [MLN], liver, and spleen), mitogen responsiveness (MLN, Peyer's patches, and spleen), and xanthine oxidase measurements (ileum and cecum). Separate groups were evaluated for survival. Both the saline and endotoxin‐challenged mice had lost about 30% of their body weight after 21 days on the low‐protein diet. The protein‐malnourished mice were more susceptible to endotoxin‐induced mortality (70% at 21 days) than the normally nourished mice (0%) (p<.001). The mitogen responsiveness of the protein‐malnourished mice to the T‐cell mitogens (PHA and Con‐A) progressively decreased the longer the mice were protein malnourished, and this decrease in blastogenic responsiveness was associated with histologic evidence of lymphoid atrophy. In contrast, the blastogenic response to the primarily B‐cell mitogen, PWM, was largely preserved. The endotoxin challenge further depressed the immune state of mice tested after 0, 7, or 14 (but not 21) days of protein malnutrition. Thus, both protein malnutrition and endotoxin impaired systemic and gut‐associated immune responsiveness to mitogens. However, in the protein‐malnourished. mice, the degree of immune suppression did not correlate with endotoxin‐induced mortality. (Journal of Parenteral and Enteral Nutrition16:25–31, 1992)