Aim The aim of this study was to investigate the association between HLA-DRB1 and DQA1 / DQB1 genetic polymorphisms in leprosy patients and their domiciliary contacts from Southern Brazil. Methods This study was conducted with 183 leprosy patients and 238 healthy controls that had prolonged contact with the patient but are not blood relatives. The polymorphisms DRB1 and DQA1 / DQB1 genes were analyzed by PCR-SSOR, using the Luminex® technology. The DQA1 / DQB1 and HLA-DRB1 (High Resolution) genotypes were used LABType® SSO Kit. Statistical analysis was performed using the Chi-square with the Yates’s or Fisher’s exact test, and Bonferroni correction ( Pc ) was also applied. This study was approved by the Ethics Committees. Results The sample evaluated was in HW Equilibrium. The allelic group frequencies showed that DQA1 ∗ 03, DQB1 ∗ 03 and DRB1 ∗ 04 were significantly higher in the control group than in patients leprosy per se ( DQA1 ∗ 03 = 17.2% vs. 11.8%, OR = 0.6, 95% CI 0.4–0.95, P = 0.026, Pc = 0.16), ( DQB1 ∗ 03 = 33.2% vs. 26.5%, OR = 0.7, 95% CI 0.5–0.98, P = 0.043, Pc = 0.25) and ( DRB1 ∗ 04 = 14.9% vs. 8.2%, OR = 0.5, 95% CI 0.3–0.8, P = 0,003, Pc = 0.046), respectively. A protective association was also observed between the multibacillary (MB) clinical form and the DRB1 ∗ 04 and DQA1 ∗ 03 alleles, while DQA1 ∗ 1 was associated with susceptibility (47.3% vs. 39.5%, OR = 1.4, 95% IC 1.0–1.8, P = 0.038, Pc = 0.232). The DRB1 ∗ 14- DQA1 ∗ 01- DQB1 ∗ 06 haplotype was associated with susceptibility to leprosy per se (1.1% vs. 0%, OR = 11.8, 95% IC 1.95 – undefined, P = 0.03, Pc = 0.39) and to the MB clinical form (1% vs. 0%, OR = 11.3, 95% IC = 1.4 – undefined, P = 0.043, Pc = 0.56). In addition, DRB1 ∗ 15:02 and DQB1 ∗ 06:01 alleles were associated with susceptibility to leprosy per se and to the MB form. On the other hand, DQA1 ∗ 03:01 (1.4% vs. 5.0%, OR = 0.3, 95% IC = 0.9–0.7, P = 0.004, Pc = 0.03) and DQB1 ∗ 03:02 (4.4% vs. 10.5%, OR = 0.4, 95% IC = 0.2–0.7, P = 0.001, Pc = 0.009) suggests a protective association to leprosy per se and the MB form compared to controls. Conclusion This study confirmed that polymorphisms in DQA1/DQB1 and DRB1 genes may influence the development/protection of leprosy and also have some influence in clinical forms of the disease.