Variants in the CDH13 gene have been identified as determinants of blood levels of adiponectin, an insulin-sensitizing adipokine. However, their association with other metabolic risk factors remains unclear. We examined variants at CDH13 in relation to total and high-molecular-weight (HMW) adiponectin using data from a genome-wide association study performed in 2,434 Singaporean Chinese with replication in up to 3,290 Japanese and 1,610 Koreans. The top signal rs4783244 in CDH13 showed strong associations with total adiponectin (standardized β [β] = −0.34, 95% CI −0.38 to −0.30, P = 2.0 × 10⁻⁷⁰), HMW adiponectin (β = −0.40, 95% CI −0.43 to −0.36, P = 1.1 × 10⁻¹¹⁷), and the HMW-to-total adiponectin ratio (β = −0.44, 95% CI −0.49 to −0.40, P = 3.2 × 10⁻⁸³). In the replication study, this single nucleotide polymorphism explained 4.1% of total and 6.5% of HMW adiponectin levels. No association was observed between rs4783244 and metabolic traits associated with insulin resistance before adjustment for HMW adiponectin levels. After adjustment for HMW adiponectin levels, the minor allele was associated with lower BMI (β = −0.15, 95% CI −0.19 to −0.11, P = 3.5 × 10⁻¹⁴), homeostasis model assessment-insulin resistance index (β = −0.16, 95% CI −0.20 to −0.12, P = 9.2 × 10⁻¹⁶), and triglycerides (β = −0.16, 95% CI −0.19 to −0.12, P = 1.3 × 10⁻¹⁶) and with higher HDL (β = 0.16, 95% CI 0.12 to 0.19, P = 2.1 × 10⁻¹⁷). CDH13 variants strongly influence plasma total and HMW adiponectin levels in East Asian populations but appear to alter adiponectin sensitivity, resulting in better metabolic health than expected based on circulating adiponectin levels.