A common cross-neutralization epitope for human papillomavirus types 6 and 16 (HPV 6 and 16) is present in the region of amino acids (aa) 108-120 of HPV-16 minor capsid protein, L2. We nasally immunized Balb/c mice with a synthetic peptide with the 13 aa HPV 16 L2 sequence, and examined the antibodies elicited. ELISA showed that the immunization induced predominantly IgG and IgA antibodies cross-binding to L1/L2-capsids of HPVs 6, 16, and 18 in sera and in vaginal secretions, respectively. The serum containing the IgG antibody and the vaginal wash containing the IgA antibody neutralized HPV 16 pseudovirions and HPV 11 authentic virions, as shown by surrogate infectivity assays. From their cross-binding activity for HPV 16 and 18, the peptide-induced antibodies can probably cross-neutralize most of the genital HPVs. The peptide-induced neutralizing activity in vaginal wash was comparable to that induced by nasally immunization with HPV 16 L1-capsids. Unlike Balb/c, C57BL/10, which has different MHC class II, did not respond to the peptide immunization, but aa substitutions in the peptide to fulfill the requirement for the C57BL/10 agretope rendered the modified peptides immunogenic. The results provide a basis for development of a peptide vaccine against broad-spectrum of genital HPVs for humans.