Adiponectin has been associated with low diabetes risk. The metabolic effects of adiponectin are mediated by adiponectin receptors 1 (ADIPOR1) and 2 (ADIPOR2). We conducted a prospective, nested case-control study of 714 cases of type 2 diabetes and 1,120 control subjects. Six polymorphisms in ADIPOR1 and 16 polymorphisms in ADIPOR2 were determined. Haplotypes inferred from ADIPOR1 polymorphisms were significantly associated with diabetes risk (overall test, -2log-likelihood = 15.1 on 5 df; P = 0.0098). A single copy of haplotype 001100 (0, common allele; and 1, minor allele) was associated with 24% decreased risk (odds ratio [OR] 0.76 [95% CI 0.61-0.96], P = 0.02) compared with the most common haplotype, 110000, adjusting for age, BMI, and other covariates. A 3' untranslated region (UTR) polymorphism, rs1139646, showed the strongest and nominally significant association with greater diabetes risk (unadjusted OR 1.26 [1.03-1.53] and adjusted OR 1.36 [1.10-1.70]). However, such an association became marginal after controlling for multiple comparisons by permutation test (P = 0.08 on the basis of 10,000 permutations). There were not significant associations between ADIPOR2 polymorphisms, individually or in haplotypes, and the risk of type 2 diabetes. In conclusion, our data indicate significant associations between ADIPOR1 haplotypes and diabetes risk but do not support a relation between ADIPOR2 variability and the disease.