DNA typing was performed on 24 Japanese patients with early-onset periodontitis (EOP) using the PCR-RFLP method to investigate an association of the susceptibility to EOP with the particular HLA class II alleles (HLA-DRB1, -DQA1, and -DQB1). DRB1*1401, DRB1*1501, DQB1*0503, and DQB1*0602 were found more frequently ("susceptible") in the EOP patients than in healthy controls. In contrast, DRB1*0405 and DQB1*0401 were found less frequently ("resistant") in EOP patients. All patients carrying DQB1*0602 had an atypical BamHI site in the intron upstream of the third exon of the DQB1 gene, which in our previous studies appeared to be a susceptible marker for EOP. A comparative analysis of the amino acid sequences of these susceptible and resistant HLA-DRB1 and DQB1 alleles elucidated some differences in antigen-derived peptide binding sites related to the susceptible or resistant alleles. Especially, DQB1*0503 and DQB1*0602 alleles carrying aspartic acid at position 57 and glycine at position 70 are increased significantly in EOP. Since amino acid residues at positions 57 and 70 on the DQB1 molecule are supposed to be involved in antigen binding, amino acid substitutions at these positions may affect the immune responsiveness to the periodontopathic antigen. Our results suggest that the DQB1 molecule plays a crucial role in the pathogenesis of EOP and that the susceptibility to EOP may be determined by the binding ability between the peptide and HLA-DQ antigens.