The protective role of the spleen in gram-positive infections, particularly in infancy and childhood, is well established. Since it is not known whether the spleen is protective in gram-negative sepsis, particularly in elderly individuals as compared to young subjects, the following study was undertaken. Splenectomized and nonsplenectomized Swiss Webster mice, 3 months old (young), or 12 months old (elderly) were utilized. Splenectomy was performed 4 weeks prior to administration of E coli endotoxin. Mortality in elderly nonsplenectomized mice was significantly greater than that of young nonsplenectomized mice. Prior splenectomy significantly increased the mortality in young mice at 48 h, whereas the mortality of E coli endotoxemia (ECE) in elderly mice was not altered by prior splenectomy. The spleen, therefore, appears to have a protective role for young mice but does not protect elderly mice with ECE. It is postulated that this loss of splenic protection reflects deteriorating splenic function with age.