Objective:To analyze the characteristics of immune cross-reaction between herpes simplex virus type 1 (HSV-1) and HSV-2 in terms of serology and clinical protection aiming to provide data for the control and prevention of diseases caused by the two viruses.Methods:An attenuated HSV-1 strain M3 was used to immunize BALB/c mice. Specific immune responses indicated by the production of neutralizing antibodies were detected. Wild-type HSV-1 and HSV-2 strains were respectively used to infect the mice through different ways 28 d after the immunization to observe the protective immunity in the M3-immunized mice against HSV-1/2 infection.Results:M3 strain could not induce specific neutralizing antibodies against HSV-2. Therefore, viral loads in tissues of the immunized mice increased significantly following different modes of HSV-2 exposure. However, no obvious abnormal clinical manifestations were found and the histopathological damage was only slight inflammatory reaction. In contrast, HSV-1-specific neutralizing antibodies were elicited in the M3-immunizaed mice with significant protective effects against HSV-1 infection.Conclusions:The immune response induced by attenuated HSV-1 strain M3 in mice exhibited immune-protective effects characterized by production of neutralizing antibodies and inhibition of virus proliferation in vivo against wild-type HSV-1 infection. For HSV-2, instead of neutralizing virus in form of antibodies, it featured by more of clinical cross-immunoprotective abilities to control virus growth.