Sporothrix brasiliensis is the most virulent fungus of the Sporothrix complex and is the main species recovered in the sporotrichosis zoonotic hyperendemic area in Rio de Janeiro. A vaccine against S. brasiliensis could improve the current sporotrichosis situation. Here, we show 3 peptides from S. brasiliensis immunogenic proteins that have a higher likelihood for engaging MHC-class II molecules. We investigated the efficiency of the peptides as vaccines for preventing subcutaneous sporotrichosis. In this study, we observed a decrease in lesion diameters in peptide-immunized mice, showing that the peptides could induce a protective immune response against subcutaneous sporotrichosis. ZR8 peptide is from the GP70 protein, the main antigen of the Sporothrix complex, and was the best potential vaccine candidate by increasing CD4(+) T cells and higher levels of IFN-gamma, IL-17A and IL-1 beta characterizing a strong cellular immune response. This immune environment induced a higher number of neutrophils in lesions that are associated with fungus clearance. These results indicated that the ZR8 peptide induces a protective immune response against subcutaneous sporotrichosis and is a vaccine candidate against S. brasiliensis infection.FAPESPUniv Sao Paulo, Fac Pharmaceut Sci, Dept Clin & Toxicol Anal, Sao Paulo, BrazilUniv Sao Paulo, Inst Chem, Dept Biochem, Sao Paulo, BrazilUniv Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo, BrazilUniv Fed Sao Paulo, Inst Environm Chem & Pharmaceut Sci, Dept Biol Sci, Diadema, BrazilUniv Fed Sao Paulo, Inst Environm Chem & Pharmaceut Sci, Dept Biol Sci, Diadema, BrazilFAPESP: 2016/04729-3Web of Scienc