The development of an effective norovirus vaccine likely requires the capacity to protect against infection with multiple norovirus strains. Advanced recombinant genetic systems and the recent discovery of a mouse-tropic norovirus strain (MNV) provide robust model systems for vaccine efficacy studies. We coadministered multivalent norovirus-like particle (VLP) vaccines with alphavirus adjuvant particles to mice and evaluated homotypic and heterotypic humoral and protective immunity to human and murine norovirus strains. Multivalent VLP vaccines induced robust receptor-blocking antibody responses to heterologous human strains not included in the vaccine composition. Inclusion of alphavirus adjuvants in the inoculum significantly augmented VLP-induced systemic and mucosal immunity compared to the responses induced by low-dose CpG DNA, validating the utility of such adjuvants with VLP antigens. Furthermore, multivalent vaccination, either including or excluding MNV VLP, resulted in significantly reduced viral loads following MNV challenge. Passive transfer of sera from mice monovalently vaccinated with MNV VLP to immunodeficient or immunocompetent mice protected against MNV infection; however, adoptive transfer of purified CD4(+) or CD8(+) cells did not influence viral loads in murine tissues. Together, these data suggest that humoral immunity induced by multivalent norovirus vaccines may protect against heterologous norovirus challenge.