Morphea is a disorder limited to the skin, characterized by a stable oval plaque with a glossy plane surface that feels indurated on palpation. In contrast, systemic sclerosis is additionally characterized by disseminate cutaneous engrossment, sclerodactyly, the presence of Raynaud's phenomenon, and internal organ involvement. Human leukocyte antigen (HLA)-DR4 class Ⅱ alleles are associated with morphea in Caucasians, whereas, HLA-DR4 presents as high frequency in Amerindians, besides it was associated with autoimmune disease. The aim of this study was to determine HLA-DR alleles in Mexican patients with morphea. This study recruited 24 morphea patients, whose HLA alleles frequencies were compared with HLA alleles frequencies presented in 22 systemic sclerosis patients and 99 ethnically matched healthy controls. The HLA-DRβ1 locus was genotyped based on the hybridization technique. HLA-DR4 and DR8 frequencies showed increases in morphea patients compared with healthy controls, whereas HLA-DR4 exhibited a statistical association with morphea when allele frequencies were compared with systemic sclerosis patients. Thus, HLA-DRβ1 associations varied in morphea and systemic sclerosis, suggesting the participation of different immunological molecular mechanisms.