The objective of this study was to determine whether a DNA prime-protein boost immunization against the Bacillus anthracis protective antigen (PA) and lethal factor (LF) antigens could induce a protective immune response against significant aerosol challenge in the rabbit model. Rabbits were vaccinated with different regimens of DNA vaccines (Table 1) and aerosol challenged with B. anthracis spores, Ames strain, with an average dose of 50 LD(50s) with a range from 18 to 169 LD(50s.) Of the five vaccinated rabbits that survived, two were immunized intramuscularly (i.m.) with DNA followed with a protein boost and three were immunized subcutaneous (s.q.) with recombinant protein. A major factor predicting survival was the ability of the animal to mount a lasting antibody response to PA. Rabbit sera were collected prior to and following aerosol challenge and titrated for PA antibodies by indirect ELISA. The results of this study indicate that DNA-based immunization against PA and LF induces significant protective immunity against aerosol challenge in the rabbit model and compares favorably with protein-based immunization.