The gene-gene interactions between markers in the alpha2-, beta2-, and beta3-adrenergic receptor (ADR) genes and obesity-related phenotypes were studied in the Quebec Family Study (QFS) cohort. The prevalence of the Arg allele of the Arg16Gly polymorphism in the beta2-ADR gene was higher (49%) in males with a body mass index (BMI) of 35 kg/m2 or higher versus those with a BMI less than 35 kg/m2 (33%; P = .010). The beta2-ADR gene Arg16Gly and Gln27Glu polymorphisms were associated with plasma total and low-density lipoprotein (LDL) cholesterol concentrations. In addition, the homozygotes for the 6.3-kb allele of DraI polymorphism in the alpha2-ADR gene had the lowest mean abdominal subcutaneous fat area (P = .012) and total fat area (P = .003), as well as insulin area, under the curve during an oral glucose tolerance test ([OGTT] P = .004). Several ADR gene-gene interaction effects on abdominal fat distribution and plasma lipids were detected. First, significant interactions between alpha2- and beta3-ADR genes were observed on total (P = .015) and subcutaneous (P = .004) abdominal fat. Second, interaction effects between alpha2- and beta2-ADR gene variants influenced total, high-density lipoprotein (HDL), and LDL cholesterol concentrations. Finally, there were interactions between markers within the beta2-ADR gene affecting plasma triglyceride concentrations and subcutaneous abdominal fat. From these results, we conclude that polymorphisms in the ADR genes contribute to body fat and plasma lipid variability in men. Gene-gene interactions among the ADR genes contribute to the phenotypic variability in abdominal obesity and plasma lipid and lipoprotein, but not in visceral fat levels.