The invention discloses a streptococcus-suis-disease-resistant fusion protein with the autoimmune activity and preparing and application thereof. The fusion protein is composed of Omp16<26-168> peptide located at the amino terminal and Sao<28-138> peptide located at the carboxyl terminal. The Sao<28-138> peptide is an amino acid fragment which is exposed out of a streptococcus suis cell in a Sao protein molecule, has the immunogenicity, and is highly conservative between different strains and subtypes, and the Omp16<26-168> peptide is an amino acid fragment is exposed out of a Brucella cell in a Omp16 molecule, has the TLR4 activating activity, and is free of Lipobox (the Lipobox is lowly toxic or completely nontoxic). Mice are subjected to an immunity virus attacking test through the Omp16<26-168>/Sao<28-138> fusion protein, it is shown that the Omp16<26-168>/Sao<28-138> fusion protein has the good immune protection effect, a quite-high cellular immune response and a quite-high humoral immune response can be induced, but a Th1 response is the main response, and the fusion protein has the self-adjuvant effect, is an ideal vaccine antigen of streptococcus, and has the important value in development and application aspects of novel vaccine.