Objective To explore the genetic association of human leucocyte antigen (HLA) -DRB1 and HLA-DQB1 allele polymorphisms with pemphigus. Methods Fifty-eight patients with pemphigus (case group) and 89 normal controls (control group) were selected in Shanghai as study objectives. HLA-DRB1 and HLA-DQBl alleles in two groups were typed by polymerase chain reaction-sequence specific primers (PCR-SSP). Direct count method was adopted to calculate allele frequencies, and comparison was performed between groups. Odds ratios (OR) of allele frequencies were used to evaluate the association of gene with disease. Results A total of 13 HLA-DRB1 alleles and 5 HLA-DQB1 alleles were detected in case group and control group. The frequencies of HLA-DRB1x14 allele and HLA- DQB1 * 05 allele in case group were significantly higher than those in control group (17.24% vs 1.69%, P=0.000, Pc < 0.05, OR = 12.150; 18.97% vs 6.74%, P =0.001, Pc< 0.05, OR =3.238). The frequency of HLA-DQBl * 06 allele in case group was significantly lower than that in control group (15.52% vs 30.90%, P=0.003, Pc<0.05, OR=0.411). Conclusion HLA-DRB1 * 14 and HLA-DQBl * 05 may be predisposing genes, while HLA-DQBl * 06 may be protective gene of pemphigus in Shanghai.