Host factors play an important role in determining the immune response and development of leprosy. The human leukocyte antigen system (HLA) has repeatedly been found to be associated with the pathogenesis of leprosy. This study analyzes the polymorphism of the HLA class I and II antigens in multibacillary leprosy patients and a healthy control group to provide predictable prognostic indicators and/or a differential diagnostic for the disease. Sixty-5 multibacillary leprosy patients from Lo-Sheng Leprosarium and 190 healthy Taiwanese were used as cases and controls, respectively. A serologic method was initially used for HLA-A and HLA-B antigen determination, and sequence-based typing was later applied for HLA-DRB1 allele typing. Although no significant associations were found with HLA-A or HLA-B antigens, this study shows a strong HLA-DRB1*0405 association with resistance to multibacillary leprosy, supporting results previously reported in the literatures.