The goal of this study is to assess the protective efficiency of the E_72-296 protein, a candidate for a safer rubella virus vaccine. BALB/c mice were immunized with purified E_72-296 protein, RV JR23 strain or Attenuated RV Vaccine. Anti-RV antibodies were tested by indirect ELISA, and cell immune responses were examined by lymphocyte proliferation assay. NK cell activity and challenge tests were assayed to evaluate the safety of the E_72-296 protein. In this study, the RV-specific ELISA antibodies induced by the E_72-296 protein were obtained. Mice immunized with the E_72-296 protein had effective protection against RV when challenged with RV JR23 ten days after triple immunization. Further analyses of cell-mediated immune responses showed that the E_72-296 protein induced positive cell-mediated immunity (CMI) (stimulation index ³2.0 ). In addition, it was noticed that E_72-296 protein could not alter splenic NK cell cytotoxicity, which was reduced in mice immunized with the Attenuated RV Vaccine. This suggested that E_72-296 protein was safer than latter. These results indicated that the E_72-296 protein not only induced complete protection against RV challenge in mice, but is also a candidate for a safer vaccine.