An increase in cervical intraepithelial neoplasia (CIN) has been described in American Indian women in New Mexico. Differences in human leukocyte antigen (HLA) alleles have been reported in cervical intraepithelial neoplasia (CIN) compared with controls in other populations. We investigated HLA alleles and CIN in Southwest American Indian women. The case control study included 89 women with biopsy-proven CIN II/III (diagnosed November 1994 through October 1997) and 271 similar women with normal cervical epithelium from the same clinics. DRB1, DQB1, and DPB1 alleles were determined using DNA typing techniques. DQA1 and HLA-A allele typing was included for some subjects (randomly chosen n = 37 and n = 163 cases and controls, respectively). We found a decreased risk of CIN with DRB1*1402 (OR 0.5, 95% CI 0.3-0.9) and an increased risk with DRB1*1501 (OR 2.7, 95% CI 0.9-7.3). Additionally, DQA1*0102 was associated with increased risk (OR 4.5, 95% CI 1.3-5.3) and HLA-A*02 with decreased risk (OR 0.4, CI 0.2-0.9). Our findings are discussed along with studies in other populations.