Vaccine strategies that stimulate the ocular mucosal immune system (OMIS), the immune barrier that protects the surface of the eye are needed. However, most vaccines fail to induce local ocular immune responses and, in the absence of adjuvant, may induce a state of immunological tolerance. In this study, we present a new vaccine strategy that consists of ocular mucosal (OM) delivery of peptide epitopes, selected from the herpes simplex virus (HSV-1) glycoprotein D (gD) mixed with synthetic immunostimulatory oligodeoxynucleotides (ODNs) containing unmethylated CpG motifs (CpG2007). Repeated topical ocular application of gD peptide epitopes and CpG2007 induced peptide-specific and virus-neutralizing IgA/IgG in tears as well as in serum. As a second marker, generation of local and systemic peptide- and virus-specific T cells confirmed the potent immunogenicity of peptides-CpG2007 formulation when applied through the OM route. Moreover, OM delivery of peptides-CpG2007 induced local IFN-gamma and IL-2 responses and low IL-4 production, demonstrating the polarization towards a Th1 response. Immunization, using free CpG2007 ODNs or peptides alone did not produce OMIS stimulation. This novel vaccine strategy may be key for ocular infectious pathogens, such as HSV-1, that require both secretory antibody and the Th1 responses. The results suggest the clinical feasibility of developing an OM delivery system using epitope-based vaccines.