We investigated the development of exoerythrocytic forms (EEF) of Plasmodium berghei in livers of normal and macrophage-depleted Brown Norway rats. Macrophages were depleted by use of liposome-encapsulated dichloromethylene diphosphonate. Upon inoculation of sporozoites, macrophage-depleted rats had significantly larger numbers of EEF than untreated rats. We also investigated the effect of macrophage impairment by silica treatment on the development of EEF and confirmed that silica induces a significant reduction of EEF development. Intravenous administration of silica induced high levels of interleukin-6 in plasma within a few hours. The seemingly contradictory results for EEF development may be explained by our previous observation that interleukin-6 strongly inhibits sporozoite penetration and EEF development in vivo. We conclude that in experimental infections with sporozoites, Kupffer cells inhibit rather than enhance EEF development.