Malaria remains a grave concern for humans, as effective medical countermeasures for
Plasmodium
infection have yet to be developed. Phagocytic clearance of parasitized red blood cells (pRBCs) by macrophages is an important front-line innate host defense against
Plasmodium
infection. We previously showed that repeated injections of low-dose lipopolysaccharide (LPS) prior to bacterial infection, called LPS preconditioning, strongly augmented phagocytic/bactericidal activity in murine macrophages. However, if LPS preconditioning prevents murine
Plasmodium
infection is unclear. We investigated the protective effects of LPS preconditioning against lethal murine
Plasmodium
infection, focusing on CD11b
high
F4/80
low
liver macrophages, which are increased by LPS preconditioning. Mice were subjected to LPS preconditioning by intraperitoneal injections of low-dose LPS for 3 consecutive days, and 24 h later, they were intravenously infected with pRBCs of
Plasmodium yoelii
17XL. LPS preconditioning markedly increased the murine survival and reduced parasitemia, while it did not reduce TNF secretions, only delaying the peak of plasma IFN-γ after
Plasmodium
infection in mice. An
in vitro
phagocytic clearance assay of pRBCs showed that the CD11b
high
F4/80
low
liver macrophages, but not spleen macrophages, in the LPS-preconditioned mice had significantly augmented phagocytic activity against pRBCs. The adoptive transfer of CD11b
high
F4/80
low
liver macrophages from LPS-preconditioned mice to control mice significantly improved the survival after
Plasmodium
infection. We conclude that LPS preconditioning stimulated CD11b
high
F4/80
low
liver macrophages to augment the phagocytic clearance of pRBCs, which may play a central role in resistance against
Plasmodium
infection.