The Plasmodium falciparum proteins serine repeat antigen (SERA) and serine repeat protein homologue (SERPH) have similarity in sequence with cysteine proteases in a well-conserved protease domain. We identified three SERA homologues from the murine malaria parasite Plasmodium vinckei and evaluated immune responses to the protease domains of these proteins. Mice that developed protective immunity to P. vinckei after serial infection and cure demonstrated humoral and cell-mediated responses against the SERA homologue protease domains. Mice immunized with Salmonella typhimurium expressing the protease domain of one of these antigens demonstrated cellular responses against the antigen and increased survival against lethal challenge with P. vinckei. Our results suggest that the protease domains of SERA and SERPH are worthy of additional study as potential components of a malaria vaccine.