Until recently, neuromyelitis optica (NMO) was considered to be a sub-type of multiple sclerosis (MS), which has a strong predilection for Caucasian populations, whereas NMO is more frequent in non-Caucasian individuals. The objective of this study was to compare the HLA-DRB profile in Brazilian Mulatto patients with NMO spectrum disorders (NMOSDs) with that observed for Mulatto MS patients and healthy Mulatto controls. Twenty seven NMOSD patients (20 women), all seropositive for NMO-IgG, 29 MS patients and 28 Mulatto healthy blood donors were evaluated for HLA-DRB allele groups. HLA-DRB1*03 allele group was overrepresented in NMO patients compared with healthy controls (p = 0.0401; OR = 3.23, 95%CI: 1.07—9.82). In contrast, the HLA-DRB1*15 allele group was overrepresented in Brazilian MS patients (OR = 15.89, 95%CI: 3.51—71.85; p < 0.0001). DRB3 was overrepresented in NMO (p = 0.0064), and DRB5 overrepresented in MS patients (p = 0.0001). The low frequency of HLA-DRB1*15 alleles was associated with the presence of long and central cord lesions at magnetic resonance. In addition, DRB1*15 alleles were associated with the fulfillment of the Barkhof criteria. In conclusion, these results indicate that the DRB profile of NMO patients is different from that observed for MS patients, further corroborating the distinction between NMO and MS.