The association between human leukocyte antigen (HLA) class II antigens and celiac disease (CD) was analyzed in a Spanish population. No association with DRB1*04 and DQB1*0302 was noted. The main associated haplotype (70.8%) was DRB1*03-DQB1*0201-DQA1*0501(DR3-DQ2), followed by DRB1*07-DQB1*0202-DQA1*0201 (DR7-DQ2) haplotype, which is associated with DRB1*11-DQB1*0301-DQA1*0505 (DR11-DQ7). The combinations of DR3-DQ2 with DR7-DQ2, and DR7-DQ2 with DR11-DQ7, present a twofold risk compared with each haplotype in homozygosis. An independence test in DR3-DQ2 haplotype found that association with CD was attributable to the whole haplotype, but for DR7-DQ2 was secondary to DQB1/DQA1. There is no need of a double gene dosage to increase the risk. CD-associated alleles typing demonstrates a very high negative predictive value to exclude CD in risk groups.