The aim of the study was to investigate the possible interactions among the glucocorticoid receptor (GRL), lipoprotein lipase (LPL), and adrenergic receptor (ADR) genes on plasma insulin and lipid levels. The study was cross-sectional and based on 742 individuals from phase 2 of the Quebec Family Study (QFS) cohort. Gene markers were identified by Southern blot analysis or polymerase chain reaction (PCR). Plasma glucose and insulin in the fasted state and during an oral glucose tolerance test (OGTT) were determined and insulin and glucose areas were computed. Triglyceride (TG) and cholesterol concentrations in plasma and lipoprotein fractions were determined enzymatically. The results show that GRL and LPL variants had independent effects on plasma high-density lipoprotein cholesterol (HDL-C) and two β2-ADR variants were related to total cholesterol concentrations. The α2-ADR gene Dral polymorphism was the only variant that had an independent effect on the plasma insulin area. Gene-gene interaction effects were found between GRL and α2-ADR genes for low-density lipoprotein cholesterol ([LDL-C] P = .013) and between GRL and LPL genes for HDL-C (P = .045). Higher-order interaction effects involving GRL, LPL, and ADR markers were observed for the plasma insulin area (P = .001 to .025) but not the glucose area. After correction for multiple tests, the findings remained essentially unchanged for the insulin area but became nonsignificant for the lipid phenotypes. In conclusion, multiple interactions among GRL, LPL, and ADR gene markers contribute to insulin metabolism and perhaps to lipid levels, while no significant effect is found for each gene separately. The LPL locus appears to determine the pattern of interactions with ADR and GRL loci. These results suggest that gene-gene interaction effects could play a role in the etiology of risk factors for common chronic diseases.