Abstract Context: Serum levels of resistin are believed to modulate insulin resistance in humans. Objective: The aim of this study was to investigate whether serum resistin levels are genetically controlled and whether this control is shared with other insulin resistance traits. Design and Methods: The study cohort included 264 nondiabetic probands, Caucasian from Italy, and their 473 adult family members. Phenotypic characterization included anthropometric variables, blood pressure, fasting glucose and insulin, lipid profile, and resistin levels. Genotypes were determined at position g.−420C→G (rs1862513), IVS2+181G→A (rs3745367), and GAT(n) polymorphisms of the resistin (RETN) gene. Results: In the 264 unrelated probands, resistin levels were significantly (P < 0.01) correlated with adiposity, blood pressure, C-reactive protein, and the metabolic syndrome score. In a variance component analysis of the 264 probands and their 473 relatives, about 70% of the observed variation of serum resistin levels was heritable (P < 0.0001). A small, but significant (P = 0.004) proportion of this variance was explained by the G→A variation at position IVS2+181 of the RETN gene. Significant genetic correlations (P < 0.05) were observed between resistin and body mass index (ρg = 0.30), waist circumference (ρg = 0.32), the insulin resistance index HOMAIR (ρg = 0.28), and the metabolic syndrome score (ρg = 0.35). Conclusions: These data indicate that serum resistin is highly heritable and has some common genetic background with traits related to insulin resistance, reinforcing the hypothesis that this adipokine may play a pathogenic role in insulin resistance-related abnormalities, including type 2 diabetes and cardiovascular disease.