Depletion of mouse Kupffer cells and splenic macrophages following intravenous administration of liposome-entrapped clodronate severely reduced host resistance to primary infection with Listeria monocytogenes. Infection of clodronate-treated mice with a sublethal dose of L. monocytogenes resulted in death of the mice within 3 days. The macrophage depletion resulted in marked increases in bacterial growth in the liver and spleen, but not in other tissues. The proliferation of L. monocytogenes was observed in a large number of hepatocytes that underwent apoptosis. Infiltration of neutrophils in the liver and rapid formation of microabscesses were observed in the control mice after L. monocytogenes infection. However, there was less accumulation of neutrophils in the liver of Kupffer cell-depleted mice than in the control mice. Expression of macrophage inflammatory protein-2 (MIP-2) was enhanced in the livers of both the control and Kupffer cell-depleted mice after L. monocytogenes infection. MIP-2 was also induced in a murine hepatocyte cell line following L. monocytogenes infection. The administration of neutralizing anti-interleukin-8 receptor homolog antibody severely abrogated neutrophil infiltration into the Listeria-infected mouse liver. Anti-MIP-2 antibody moderately reduced neutrophil infiltration and microabscess formation in the liver. These findings indicate that Kupffer cells protect hepatocytes from L. monocytogenes infection and the resultant apoptosis. Moreover, MIP-2 and its related molecules produced by the infected hepatocytes regulate neutrophil infiltration and microabscess formation in primary listeriosis.