The host genetic background has been considered one of the factors that influence leprosy outcome, a chronic infectious disease caused by Mycobacterium leprae. Genome scans demonstrated that the 6p21 region is associated with leprosy and a substantial number of population-based studies analyzing human leukocyte antigen (HLA) class II loci suggested association of HLA-DR with leprosy. However, some studies lacked robustness as they had limited power. Indeed, experimental designs require increased sample size to achieve adequate power, as well as replication studies with independent samples for confirmation of previous findings. In this work, we analyzed the influence of the HLA-DRB1 locus on leprosy susceptibility per se and disease type using a case-control design carried out in Brazilians (578 cases and 691 controls) and a replication study based on a family design in a Vietnamese population (n=194 families). The results showed that HLA-DRB1*10 is associated with susceptibility to leprosy and HLA-DRB1*04 is associated with resistance, both in the Brazilian and Vietnamese populations suggesting that these alleles play an important role in the activation of cellular immune responses against M. leprae.