In spite of long-term antibiotic prophylaxis and pneumococcal vaccination, there still exists a proportion of highly susceptible splenectomized or functionally hyposplenic patients at risk of contracting fatal overwhelming infections. We have studied the effect of gammaglobulin prophylaxis in experimental sepsis among splenectomized rats. Administration of 37.5 mg human gammaglobulin/kg body weight 24 h before challenge with 10(3) pneumococci resulted in the survival of 19 of 24 rats, in contrast to 1 of 24 controls. A dose of 19 mg/kg body weight was not protective (7 of 23 survived). However, treatment with penicillin 18 h after challenge in the gammaglobulin-pretreated group of animals saved 21 of 24 animals, although penicillin without gammaglobulin prophylaxis showed no effect. These data indicate that even relatively low circulating concentrations of specific antibody after gammaglobulin prophylaxis might nonetheless be adequate to render septic disease easier to treat.