Children born large for gestational age (LGA) may be at risk for development of obesity and insulin resistance (IR). The reciprocal relationship of adipokines and proinflammatory cytokines is suggested to play a putative role in fine tuning of insulin secretory dynamics. To evaluate serum interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), leptin, insulin-like growth factor-1 (IGF-1), and IGF-binding protein-1 (IGFBP-1) concentrations in idiopathic LGA-born children to appropriate for gestational age (AGA) and idiopathic LGA-born children at prepubertal ages and investigate their associations with IR, evaluated by homeostasis model assessment-IR (HOMA-IR), we conducted a cross-sectional study to compare 40 (19 females) idiopathic LGA-born prepubertal children [mean +/- A SD age 6.1 +/- A 2.5 years] and 49 (25 females) (5.4 +/- A 1.8 years) AGA-born BMI-matched peers with respect to anthropometric and laboratory data. Both groups were further divided into subgroups as being obese/overweight (OW) and non-OW, and the analyses were repeated. LGA-born children were taller and heavier than AGA-born children (p < 0.001). Fasting insulin, HOMA-IR, and leptin were higher in LGA-born children than in AGA-born counterparts (p < 0.001). Serum TNF-alpha levels were lower and IL-6 levels were significantly higher in LGA- than in AGA-born children (p < 0.001). In the LGA group, TNF-alpha was correlated with HOMA-IR (r = -0.49, p = 0.002). LGA-born non-OW children had higher serum insulin concentrations and HOMA-IR than AGA-born counterparts. Multivariate regression analysis revealed that HOMA-IR was best explained by (R (2) = 0.517) birth weight SDS (beta = +0.418, p = 0.002), leptin (beta = +0.620, p = 0.000), and TNF-alpha (beta = -0.374, p = 0.003) in LGA-born children. Idiopathic LGA-born children have significantly lower TNF-alpha and higher IL-6 levels than AGA-born children. Reduced TNF-alpha levels are associated with increased IR.