Malnutrition is associated with an increased susceptibility to infection by altering host defense mechanisms. A number of investigators have demonstrated restoration of in vitro immunocompetence following nutritional repletion with intravenous hyperalimentation. This study was designed to assess in vivo host defense mechanisms following protein depletion and repletion using a septic challenge. Female Fischer rats (150 gm) were fed a regular diet or a 2% agar protein depletion (DEP) diet for 14 days. The rats were then administered an infectious challenge with intraperitoneal injections of 7 ml/kg of a solution of 10(9) organisms/ml of E. coli with 4 gm% hemoglobin as red cells. Two additional organisms were repleted by regular diet (DEP-Oral) or by an intravenous solution (DEP-TPN) of dextrose-amino acid-lipid (D25 3.75% Aminosyn, 10% Intralipid) for an additional 2-week period, and given the experimental peritonitis challenge. Normal rats challenged with E. coli-hemoglobin adjuvant peritonitis had 66% survival as opposed to 15% survival of protein depleted rats. Protein-depleted (DEP-oral) rats refed with regular diets had a 60% survival which was comparable to normal controls. Rats repleted with intravenous hyperalimentation had a mortality comparable to protein-depleted controls. The data confirm that protein depletion is associated with loss of host defense mechanisms. Although refeeding by regular diet resulted in restoration of host defense, repletion by parenteral nutrition, in this model, did not improve survival.