Irradiated sporozoites are generally thought to elicit protective immune responses that are parasite stage and species specific. But immunization with Plasmodium falciparum sporozoites delivered by the bite of infected mosquitoes protects an average of 60% mice from Plasmodium berghei sporozoite infection. Protection appears to be specific as P. falciparum sporozoite-immunized mice protected against P. berghei remain susceptible to Plasmodium yoelii sporozoite infection. Passively transferred immunoglobulin from P. falciparum sporozoite-immunized mouse serum protected naive mice against challenge with P. berghei sporozoites, indicating that cross-protection is mediated, at least in part, by anti-sporozoite antibody. Antibody-mediated protection may not be due to cross-reaction between P. falciparum and P. berghei CS proteins because mice immunized with the recombinant P. falciparum CS protein repeat vaccine candidate, R32tet32, remain susceptible to P. berghei sporozoite infection.