Polymorphism amongst the human leucocyte antigen (HLA) class II genes could influence antigen presentation and the ability to control human immunodeficiency virus (HIV)-1 by modulating the virus specific CD4 immune response. To examine the effect of such polymorphisms on disease progression, we studied a cohort of 46 HIV-1 infected long-term non-progressors (LTNPs), 87 intermediate progressors (IPs) and 26 rapid progressors. Kaplan-Meier survival analysis of all patients in the cohort on time to a CD4 count less than 350 cells/ micro l, showed a trend for a slower rate of CD4 decline in patients with, compared to those without, the DRB1*15-DQB1*06 haplotype (hazard ratio (HR) 0.69, 95% CI 0.46-1.01, P = 0.06). A similar effect was not observed with the DRB1*13-DQB1*06 haplotype (HR 1.18, 95% CI 0.75-1.88, P = 0.46), but was observed when DQB1*06 alleles were considered irrespective of their DR association (HR 0.74, 95% CI 0.52-1.05, P = 0.06). Major HLA-DQ6 alleles encode aspartate (Asp) at position 57 on the DQbeta chain, a phenotype associated with protection from other immune disorders. We therefore examined the frequency of all DQbeta57 Asp+ alleles, but could not detect a significant effect on the rate of CD4 decline. To examine whether the genotype associated with slower CD4 decline was over-represented in patients with a slow rate of disease progression, we conducted a categorical analysis of a subset of patients with an extended follow-up of 14+years. We found a higher proportion of LTNPs at 14+ years possessed the DRB1*15-DQB1*06 haplotype compared to IPs at 14+ years (38.46 versus 18.18%), though this difference did not reach statistical significance. When DQB1*06 alleles irrespective of their DR association were considered, the protective effect was greater (76.9% LTNPs versus 18.18% IPs, P = 0.04). Our results highlight the potential protective effect of HLA DQB1*06 alleles on the course of HIV disease.