Background: Human leukocyte antigen (HLA) complex is a gene family involved in antigen presentation associated with protection or susceptibility to inflammatory, infectious and autoimmune diseases. Atherosclerosis is a chronic inflammatory disease in which HLA molecules play a role in the initiation and development of the disease through presentation of self or foreign antigens to T cells. Objective: To investigate the association of HLA-DRB1 alleles with atherosclerosis in a sample of southwestern Iranians. Methods: We performed an analytical cross-sectional study involving 96 patients with atherosclerosis and 72 controls. HLA-DRB1 genotyping was performed by PCR-SSP method. Results: We observed a significantly lower frequency of DRB1*01 in patients with coronary artery atherosclerosis than in controls (4.68% vs. 13.1, P=0.0052, OR=3.09, CI 95%: 1.35-7.05). However, this allele showed a positive association with high blood pressure (P=0.009) in patients. Furthermore, DRB1*16 allele was associated with hyperlipidemia (P=0.008) in patients. Conclusion: Our results demonstrated that DRB1*01 may be a protective allele against atherosclerosis in individuals who live in southwest of Iran. The mechanism of this protection needs further investigation.