Most vaccines are delivered by injection. Mucosal vaccination would increase compliance and decrease the risk of spread of infectious diseases due to a reduction of mucosal colonization and of contaminated syringes. However, most vaccines are unable to induce immune responses when administered mucosally, and require the use of strong adjuvant or effective delivery systems. Synthetic oligodeoxynucleotides (ODN) containing CpG immunostimulatory sequences (ISS) have been shown to act as potent adjuvants of type-1 immune responses also when mucosally co-administered with protein or peptide vaccines. We have shown that ISS can increase the anti-polysaccharide polyribosyl ribitol phosphate (PRP) antibody titres and anti-diphtheria toxin neutralizing antibody, if used as adjuvant of anti-Haemophilus influenzae type b (Hib) PRP vaccine conjugated with cross-reacting material (CRM) of diphtheria toxin in mice. Here, we show that ISS have the potential to increase host local and systemic antibody response against both the PRP and the protein component of a conjugated vaccine when mucosally administered in mice. Mucosal administration of Hib-CRM vaccine induced anti-PRP and neutralizing anti-diphtheria toxin antibodies of all the IgG subclasses, with a predominance of type-1 immune response-associated IgG2a and IgG3. At odds with systemic administration, the mucosal delivery of Hib-CRM induced anti-PRP and anti-diphtheria toxin mucosal IgA. These data envisage the feasibility of a mucosal vaccination with an already licensed Hib-CRM vaccine to achieve both an anti-H. influenzae and -diphtheria effective protection.