The secreted hepatokine fetuin-A emerges as an independent predictor of type 2 diabetes in adulthood. The overall aims of this study were: (1) to investigate the associations of fetuin-A with adiposity and insulin resistance, as well as its relationship with adipokines, in prepubertal children, and, (2) to evaluate whether, in prepubertal obesity, serum fetuin-A levels may either change or predict the responsiveness to an educational-based weight excess reduction program. We studied 200 prepubertal children (boys/girls: 89/111; Tanner stage 1; age: 5-13 years), included in a cohort of 44,231 adolescents who participated in an extensive Italian school-based survey. According to Cole's criteria, 100 individuals were lean (boys/girls: 57/43) and 100 obese (boys/girls: 54/46). A subset of 53 obese individuals (boys/girls: 28/25; age: 6-12 years) were also evaluated after a weight excess reduction program. Serum fetuin-A, leptin, total and high molecular weight adiponectin levels, as well as homeostasis model assessment of insulin resistance were assessed. When compared with lean, obese children exhibited higher (aEuro dagger p < 0.0001) fetuin-A concentrations, without differences between sex. Fetuin-A was positively associated with adiposity, homeostasis model assessment of insulin resistance, and leptin levels. In multivariate analysis, the associations between fetuin-A and leptin or homeostasis model assessment of insulin resistance lost the significance after adjustment for BMI (Z-score), which, in turn, represented an independent determinant of fetuin-A (R (2) (adj) 0.327; p < 0.0001). Notably, after weight excess reduction program, fetuin-A levels dropped (aEuro dagger p < 0.0001 vs. basal). Interestingly, no significant differences of fetuin-A concentrations between responders and no responders were found. In prepubertal children, fetuin-A represents an early marker of adiposity, and its reduction after lifestyle intervention may partly contribute to the beneficial effects of weight excess reduction program.