Salmonella enteritidis was injected intravenously, intraperitoneally, or subcutaneously into specific pathogen-free mice. The number of organisms in the blood, liver, spleen, peritoneal cavity, and draining inguinal lymph node was determined by daily enumeration. Opsonization of the organism with hyperimmune serum increased the rate of phagocytosis, resulting in rapid blood clearance together with an alteration in the relative numbers of organisms accumulating in the liver and spleen. Serum treatment also brought about a substantial increase in the number of bacteria killed during the first 60 min of the infection. However, the survivors of this initial period of inactivation then multiplied rapidly in the liver and spleen, ultimately resulting in the death of the animal from a generalized infection. Attempts to passively protect mice with hyperimmune serum were uniformly negative. The effects of treatment of the virulent S. enteritidis with hyperimmune serum were consistent with the general thesis that cellular rather than humoral factors play the major role in the expression of an effective antibacterial immunity against salmonella infections.