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Plasmodium sporozoites, transmitted to the mammalian host through a mosquito bite, travel to the liver, where they invade hepatocytes, and develop into a form that is then able to infect red blood cells. In spite of the importance of innate immunity in controlling microbial infections, almost nothing is known about its role during the liver stage of a malaria infection. Here, we tested whether synthetic CpG phosphothioate (PS) oligodeoxynucleotides (ODNs), which bind to Toll-like receptor 9 (Tlr9), could have a protective effect on Plasmodium berghei infection in hepatocytes. Surprisingly, CpG PS-ODNs potently impair P. berghei infection in hepatoma cell lines independently of Tlr9 activation. Indeed, not only CpG but also non-CpG PS-ODNs, which do not activate Tlr9, decreased parasite infection. Moreover, the ability of PS-ODNs to impair infection was not due to an effect on the host but rather on the parasite itself. In fact, CpG PS-ODNs, as well as non-CpG PS-ODNs, impair parasite gliding motility. Furthermore, our analysis reveals that PS-ODNs inhibit parasite migration and invasion due to their negative charge, whereas development inside hepatocytes is undisturbed. Altogether, PS-ODNs might represent a new class of prophylactic anti-malaria agents, which hamper hepatocyte entry by Plasmodium sporozoites. [ABSTRACT FROM AUTHOR]