In response to recent outbreaks of H5N1 highly pathogenic avian influenza virus (HPAIV), the development of an effective H5N1 influenza vaccine is urgently important. We assessed the efficacy of two inactivated H5N1 whole-virus vaccines, rgHK213/03 and rgVNJP1203/04, generated by reverse genetics in a mouse model in the presence or absence of aluminum hydroxide (alum) adjuvant. Mice immunized with rgHK213/03 vaccine produced sufficient levels of serum antibodies that were cross-reactive to recent heterologous HPAIV-H5N1 virus, A/Turkey/12/06. The vaccinated mice also elicited protective immunity against challenge with both homologous and heterologous HPAIV-H5N1 viruses. These immune responses were enhanced by addition of alum adjuvant, resulting in antigen sparing of vaccine. On the other hand, mice immunized with rgVNJP1203/04 vaccine had low levels of serum antibodies and less protective immunity than that elicited with rgHK213/03 vaccine regardless of addition of alum adjuvant. Our study suggests that rgHK213/03 vaccine is still useful as a backup vaccine for recent H5N1 viruses and that if rgVNJP1203/04 vaccine is employed, more vaccine antigen would be necessary to induce sufficient immunity.