Objectives: We had reported before that CTLA4 targeted anti-caries DNA vaccine dramatically enhanced the immune responses compared wtih non-targeted anti-caries DNA vaccine. Here we compared the immunogenicity of those CTLA4 targeted anti-caries DNA vaccines encoding different-size antigens in BALB/c mice. Methods: The recombinant targeted anti-caries DNA vaccines pGJA-P/VAX encoding CTLA4-Ig-GLU-A-P (4.3kb) and pGJGLU/VAX encoding CTLA4-Ig-GLU (2.1kb) were constructed. 37 female BALB/c mice were immunized with pGJA-P/VAX or pGJGLU/VAX via intranasal administration (i.n.) or quadriceps muscle injection (i.m.). Antibody responses to GTF in both serum and saliva were detected using ELISA. Results: GTF-specific serum antibody responses in mice immunized with pGJGLU/VAX via i.m. were 3 to 4-fold higher (P<0.01) than those in mice immunized with pGJA-P/VAX via i.m. in 8 to 12 weeks after the first immunization. As to the salivary anti-GTF antibody responses, although there were no significant differences among targeted DNA vaccines,pGJGLU/VAX vaccination via i.n. induced the highest specific antibody titres in mice. Conclusions: These findings indicate that the size of antigen may affect the immunogenicity of CTLA4 targeted anti-caries DNA vaccine. pGJGLU/VAX, which encodes smaller antigen than pGJA-P/VAX, induced significantly higher serum specific IgG antibody levels than pGJA-P/VAX,which provide information to help to design the targeted anti-caries DNA vaccine and help to understand the mechanism of enhancement of CTLA4 targeted DNA vaccine. The study was supported by National Natural Scientific Foundation of China. 30271416 and 30330660