Nonencapsulated Streptococcus pneumoniae (NESp) is an emerging human pathogen that colonizes the nasopharynx and is associated with noninvasive disease such as otitis media (OM), conjunctivitis, and nonbacteremic pneumonia. For decades, expression of a polysaccharide capsule appeared to be necessary for establishment of colonization and development of invasive pneumococcal disease (IPD). Accordingly, the currently licensed pneumococcal vaccines target the polysaccharide capsule. However, NESp expressing the novel oligopeptide importer proteins AliC and AliD have been isolated during IPD. Our study reveals that NESp expressing AliC and AliD have intensified virulence compared to isogenic mutants, and we provide insight about how this pneumococcal population has become associated with IPD. Our data demonstrates that AliC and AliD enhance murine nasopharyngeal colonization and are required for OM in a chinchilla model. Furthermore, AliC and AliD increase pneumococcal survival in chinchilla whole blood and decrease deposition of human C3b on the bacterial surface. As NESp become an increasing threat to public health, our study exposes specific virulence factors to possibly target for a broadened prevention of IPD through vaccination.