The host immune response to human papillomaviruses (HPVs) is believed to be an important determinant of progression of HPV-associated cervical neoplasia. Human leukocyte antigens (HLAs) are important in the presentation of foreign antigens to the immune system. Previous studies have suggested a possible association between HLA and cervical neoplasia, but the specific alleles found to be associated with disease have varied between studies. To further evaluate this issue, we conducted a nested case-control study within a 24,000-woman cohort study in the United States. A total of 711 women were selected for the study: 141 women diagnosed with high-grade squamous intraepithelial lesions (HSILs) of the cervix; 202 women diagnosed with low-grade SILs (LSILs); 166 women with no history of cervical neoplasia, but evidence of HPV-16 infection; and 202 women with no history of cervical abnormalities and who were HPV negative during follow-up as part of our cohort. Cervicovaginal lavage samples collected from participants were used for HPV testing by L1 consensus primer PCR and the Hybrid Capture tube test methods. DNA extracted from these same lavage samples were used for PCR-based HLA genotyping. Our results suggest a positive association between HLA B7 and HLA DQB1*0302 and disease. A negative association with disease was observed for HLA DRB1*1501-DQB1*0602 and DRB1*13. Associations were strongest when analyses were restricted to HPV-16-positive cases as follows. Compared with women who were cytologically normal and HPV negative, HLA B7 was associated with a 1.5-fold increased risk of HPV/LSIL [95% confidence interval (CI) = 0.95-2.5] and a 2.5-fold increased risk of HSIL (95% CI = 1.2-5.1). HLA DQB1*0302 was associated with a 1.5-fold increased risk of HPV/LSIL (95% CI = 0.94-2.4) and a 1.7-fold increased risk of HSIL (95% CI = 0.84-3.5). HLA DRB1*1501-DQB1*0602 was associated with a decreased risk of HSIL [relative risk (RR) = 0.21; 95% CI = 0.07-0.62]. HLA DRB1*13 was associated with a decreased risk of HPV/LSIL (RR = 0.78; 95% CI = 0.51-1.2) and HSIL (RR = 0.63; 95% CI = 0.30-1.3). Individuals who were either homozygous for DQB1*0302 or carriers of both B7 and DQB1*0302 were found to be at highest risk of disease (RR = 4.5, 95% CI = 1.5-14 for HPV/LSIL; and RR = 9.0, 95% CI = 2.4-34 for HSIL). No synergistic effect was observed for the alleles found to be associated with reduced risk of cervical neoplasia. Our findings support previous studies that have found HLA B7 and DQB1*0302 to be positively associated with cervical neoplasia and are consistent with those that have suggested that DRB1*13 is negatively associated with disease, but do not confirm previous assertions that DRB1*1501-DQB1*0602 increases the risk of cervical disease.