Objective Accumulating evidence derived primarily from animal models suggests that fibroblast growth factor-21 (FGF-21) may affect the musculoskeletal system via effects on the capacity of tissues to respond to insulin. A proportion of musculoskeletal properties and underpinnings of promoting/preventing insulin resistance are established early in the pubertal transition. Thus, the objective of this study was to test the hypothesis that insulin resistance and/or obesity will promote greater FGF-21 concentration which will be inversely associated with musculoskeletal parameters [lean mass and bone mineral content (BMC)] in pre-/early pubertal children. Given the sexual dimorphic nature of musculoskeletal development of fat mass accrual, differences by obesity status and sex were also investigated. Design Cross-sectional. Patients Children ages 7-12 years (n = 69, 38% male, 48% non-Hispanic black, 45% obese). Measurements Fasting FGF-21, glucose and insulin measures were obtained. An estimate of insulin resistance was derived using the homoeostatic model assessment of insulin resistance (HOMA-IR). Body composition (BMC, lean mass and fat mass) was assessed by DXA. Multivariate regression analysis was used to evaluate the influence of FGF-21 on BMC, lean mass and HOMA-IR as dependent variables. Obesity status was established based on BMI z-score. Results FGF-21 concentrations did not differ by obesity status or by sex. There was an inverse association between FGF-21 and BMC among nonobese individuals (P = 0·01) and an inverse association between FGF-21 and lean mass among females (P = 0·02), which were both independent of fat mass. FGF-21 was inversely associated with HOMA-IR in males, but not females (P = 0·04). Conclusions The existence of relationships of FGF-21 with musculoskeletal parameters and insulin resistance raises the possibility of crosstalk between these systems. These findings suggest that circulating FGF-21 may differ in its association with bone, lean mass and insulin resistance depending on sex and weight status.