Objectives: To analyze the role of HLA-DRB1 and -DPB1 alleles in the pathogenesis of neuromyelitis optica (NMO) and multiple sclerosis in Southern Han Chinese. Methods: Thirty serum anti-aquaporin 4 antibodies (AQP4-Ab)-positive NMO patients, 53 conventional multiple sclerosis (C-MS) patients, and 93 controls (CTLs) were enrolled. The HLA-DRB1 and -DPB1 alleles of the subjects were determined by sequencing-based typing (SBT). Results: The frequency of the DRB1*0901 was lower in NMO patients than in CTLs (Puncorr=0.022, OR: 0.194, 95% CI: 0.043-0.876), and DRB1*1602 was higher in NMO patients than in C-MS (Puncorr=0.038, OR: 3.491, 95% CI: 1.024-11.896) and CTLs (Puncorr=0.051, OR: 2.711, 95% CI: 0.971-7.556). The frequency of DPB1*0501 was significant higher in NMO patients than in C-MS (Puncorr=0.018, OR: 4.629, 95% CI: 1.235-17.350) and CTLs (Puncorr=0.001, Pcorr=0.022, OR: 7.096, 95% CI: 2.011-25.044). Conclusions: DPB1*0501 correlates with risk of AQP4-Ab positive NMO in Southern Han Chinese.