Protective immunity against Streptococcus pyogenes can be induced by intranasal vaccination with the fibronectin-binding domain (H12 fragment) of the fibronectin-binding protein I (SfbI) co-administered with the B subunit of the cholera toxin (CTB) as mucosal adjuvant. However, intranasal administration of A-B moiety bacterial toxins or their derivatives has been associated with potentially severe side effects. Since the SfbI protein exhibits adjuvant properties, we investigated whether vaccination with the H12 fragment alone is sufficient to promote long-lasting protection. The obtained results demonstrated that the humoral and cellular immune responses stimulated at both systemic and mucosal levels were almost identical when mice were vaccinated with the H12 fragment in the presence or absence of CTB. Immunized mice were protected against challenge with a lethal dose of S. pyogenes given 36 or 110 days after primary vaccination to the same extent (80% survival), regardless of CTB incorporation. These results demonstrate that vaccination with the H12 fragment stimulates long-lasting protective immunity. The adjuvant properties exhibited by the fibronectin-binding domain of the SfbI protein strength the potential of this antigen for inclusion in multi-component vaccines against S. pyogenes.