The rising prevalence of the insulin resistance syndrome in our society necessitates a better understanding of the genetic determinants of all aspects of insulin action and metabolism. We evaluated the heritability of insulin sensitivity and the metabolic clearance rate of insulin (MCRI) as quantified by the euglycemic-hyperinsulinemic clamp in 403 Mexican Americans. We tested the candidate gene AMP deaminase 1 (AMPD1) for association with insulin-related traits because it codes for an enzyme that has the potential to influence multiple aspects of insulin pharmacodynamics. By converting AMP to inosine monophosphate, AMPD1 plays a major role in regulating cellular AMP levels; AMP activates AMP kinase, an enzyme that modulates cellular energy and insulin action. We determined that nine AMPD1 single nucleotide polymorphisms (SNPs) defined two haplotype blocks. Insulin clearance was found to have a higher heritability (h(2) = 0.58) than fasting insulin (h(2) = 0.38) or insulin sensitivity (h(2) = 0.44). The MCRI was associated with AMPD1 SNPs and haplotypes. Insulin clearance is a highly heritable trait, and specific haplotypes within the AMPD1 gene, which encodes a skeletal muscle-specific protein, are associated with variation in insulin clearance. We postulated that the processes of insulin action and insulin clearance in skeletal muscle are highly regulated and that AMPD1 function may play an important role in these phenomena.