Streptococcus pyogenes is a human pathogen causing invasive and non-invasive diseases, as well as severe sequels, such as rheumatic fever. Several bacterial factors have been proposed as candidate vaccine antigens. Among them, the serum opacity factor (SOF), which was able to confer protective immunity against an intraperitoneal challenge after vaccination by the parenteral route. In an attempt to develop more efficient vaccines, we combined SOF with an additional well-known protective antigen, namely, the fibronectin-binding protein I (SfbI). Intranasal immunization of mice with SOF and SfbI stimulates strong systemic and mucosal immune responses against both antigens. Animals vaccinated with SfbI, alone or in combination with SOF, were also efficiently protected against a lethal challenge with a SOF/SfbI-positive virulent S. pyogenes strain (80% survival). In contrast, those vaccinated with SOF alone were not protected against a mucosal challenge (100% lethality), which mimics more closely natural infections. These results highlight the importance of developing adequate experimental animal models to evaluate vaccine efficiency, according to the selected antigen.