Previous studies using microencapsulated neutralizing antibodies (NA) to tumor necrosis factor (TNF) and interleukin-1 (IL-1) in combination with gentamicin have demonstrated improved survival in a peritonitis model of gram-negative septic shock. Microencapsulation has been shown to improve the effectiveness of NA by delivering them intracellularly, taking advantage of the natural phagocytic activity of the macrophage. It is the purpose of this study to see if microencapsulated NA to TNF and IL-1 in combination with vancomycin can improve survival compared with NA in solution in Staphlococcus aureus-induced septic shock. Groups of 10 rats received the following treatments: (1) S. aureus plus no treatment, (2) S. aureus plus blank microspheres, (3) S. aureus plus vancomycin, (4) S. aureus plus a microsphere form of NA and vancomycin, (5) S. aureus plus a solution form of NA and vancomycin, (6) S. aureus plus a microsphere form of NA, and (7) S. aureus plus a solution form of NA. Survival was monitored for 5 days, and plasma TNF and IL-1 levels were measured for 48 h after S. aureus administration. All (100%) animals that received the microsphere form of NA plus vancomycin, 20%-70% of the animals that received the microsphere form of NA alone, and 20% of the animals that received antibiotics alone survived for 5 days or more. None of the animals in the no treatment group or blank microsphere treatment group and only 10% of the animals in the solution form of NA plus or minus vancomycin group survived for more than 5 days. Plasma TNF and IL-1 levels were significantly increased after S. aureus treatment. Simultaneous and delayed treatment with the microsphere form of NA plus or minus vancomycin significantly reduced TNF and IL-1 levels, and the solution form of NA significantly reduced only TNF levels after immediate treatment. The survival rate was higher in animals with lower TNF levels and IL-1 levels. The results demonstrate that the microsphere form of cytokine NA is 100% effective in combination with vancomycin in protecting rats from S. aureus-induced peritonitis. The microsphere form was also more efficient in attenuating both TNF and IL-1 levels.