Human cytomegalovirus (CMV) continues to be a source of severe complications in immunologically immature and immunocompromised hosts. Effective CMV vaccines that help diminish CMV disease in transplant patients and avoid congenital infection are essential. Though the exact roles of defense mechanisms are unidentified, virus-specific antibodies and cytokine responses are known to be involved in controlling CMV infections. Identifying the CMV antigens that trigger these protective immune responses will help us choose the most suitable CMV-related proteins for future vaccines. CMV envelope glycoprotein B (UL55/gB), matrix proteins (UL83/pp65, UL99/pp28, UL32/pp150), and assembly protein UL80a/pp38 are known to be targets for antiviral immune responses. We immunized mice intraperitoneally with these five CMV-related proteins for their ability to induce specific antibody responses and cytokine production in a mouse model. We observed a significant CMV-antigen-specific antibody response to UL80a/pp38 and UL83/pp65 (E/C>2.0). Mice immunized with UL80a/pp38 had significantly higher concentrations of GM-CSF, IFN-γ, IL-2, IL-4, IL-5, and IL-17A (p<0.05). Mice immunized with UL83/pp65 showed significantly higher concentrations of GM-CSF, IFN-γ, IL-2 IL-4, IL-10, IL-12, IL-17A, and TNF-α. Ratios of Th1 to Th2 cytokines revealed a Th1 cytokine bias in mice immunized with UL80a/pp38, UL83/pp65, UL32/pp150, and UL55/gB. We suggest that stimulation with multiple CMV-related proteins, which include UL80a/pp38, UL83/pp65, UL32/pp150, and UL55/gB antigens, will allow both humoral and cellular immune responses to be efficiently activated, thus serving as appropriate CMV antigens for future novel vaccines and immune-based therapeutic design.