Chronic lymphocytic leukemia (CLL) is the most frequent type of leukemia in Western countries, but its incidence is low in Asian populations. In the present study we determined the frequency of DRB1 and DQB1 alleles in 87 Iranian CLL patients and 100 healthy controls using a polymerase chain reaction (PCR) technique. An increased frequency of DRB1*07 (p = 0.04), DQB1*06 (p = 0.01) alleles, and DRB1*13/DQB1*03 haplotype (p = 0.01) and decreased frequency of the DQB1*03 (p = 0.01) allele were observed in our patients compared with healthy controls. Comparison between patients with indolent (n = 42) and progressive (n = 38) disease revealed a significant increase in DRB1*04 and DRB5 alleles in progressive patients. Similarly, a higher frequency of DRB5 (p = 0.01) allele was observed in CD38(+) compared with CD38(-) patients. Classification of the patients into immunoglobulin variable region heavy-chain genes mutated and unmutated subtypes did not reveal significant differences for the expression of any of the HLA alleles or haplotypes between these two subtypes. Our findings observed in an Iranian population indicate that CLL could be associated with distinct HLA class II alleles and haplotypes of which the DQB1*06 allele and DRB1*13/DQB1*03 haplotype have not already been reported in CLL patients from other ethnic backgrounds. Some HLA class II alleles may contribute to disease progression in CLL.