Many pathogens, including Streptococcus pneumoniae, are carried asymptomatically on the nasopharyngeal mucosa and spread among individuals by close contact. Clinical disease results when pneumococci escape from the mucosa and invade sterile sites. Although systemic immunity can prevent invasive disease, control of person-to-person spread is probably dependent on immunity acting at the mucosal surface. Intranasal immunization of mice with PspA (pneumococcal surface protein A) or a capsular 6B polysaccharide-tetanus toxoid conjugate induced mucosal and systemic antibody responses and provided long-lasting protection against carriage of S. pneumoniae. Resistance to carriage was dependent on mucosal rather than systemic immunity and was effective against heterologous strains of heterologous PspA types. Intranasal immunization with PspA also protected against systemic infection following intravenous, intratracheal, and intraperitoneal challenge.