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Zymosan-induced generalized inflammation is a convenient model to study the process of acute and chronic inflammatory processes resulting in multiple organ dysfunction syndrome. Macrophages as a source of many pro-inflammatory mediators are the major players in shock and further organ failure. Etoposide is a cytostatic drug known to reduce macrophages and monocytes in blood circulation. In the present study we have investigated whether the ability of etoposide to diminish macrophage number would have an impact on the course of zymosan-induced shock. The drug injected at a dose of 10 mg/kg 1 day before zymosan, significantly reduced the mortality and decreased the organ toxicity in Balb/c mice. Simultaneously, an inhibition of TNF-α production by alveolar and peritoneal macrophages was observed. Etoposide administered into mice with severe combined immunodeficiency (SCID) did not change the survival rate and had a little influence on organ toxicity. Our findings suggest that the beneficial action of etoposide might be attributed to the reduction of macrophages and alteration of their functions. Its effect depends on the presence of functional T and B lymphocytes. The results deserve further investigation of etoposide as a perspective therapeutic tool for inhibiting the excessive inflammatory response and to be helpful for revealing mechanisms of shock development.