Background: Fatty acid-binding protein 4 (FABP4) is an adipokine that plays a causative role in obesity and diabetes. In a stratified cross-sectional study with adolescents, we explored whether changes in FABP4 are already present in lean adolescents, provided they display elements of insulin resistance (IR). Methods: Adolescents were divided in four groups according to body mass index and homeostasis model assessment-IR. Results: In metabolically unhealthy lean (MUL) adolescents (MUL, lean with IR), FABP4 was 33% higher than in healthy counterparts (metabolically healthy lean [MHL]). Obese adolescents without IR (metabolically healthy obesity [MHO]) had 50% higher levels of FABP4 than their lean counterparts (MHL), while levels of FABP4 in obese adolescents with IR (metabolically unhealthy obese [MUO]) were 220% higher than those of MUL adolescents. The differences were significant at least with P < 0.005. MUO > MHO > MUL. Our data demonstrate that the known FABP4 defect in adults with obesity also occurs in youth and even in lean adolescents, suggesting an early association between impaired glucose metabolism and FABP4 irrespective of body weight. FABP4 was more sensitive in discerning each of our 4 subgroups than either adiponectin or leptin. Moreover, evidence for a putative early adiponectin resistance in MUL suggests a combined defect in these adolescents that call for early detection and prevention of the metabolic disturbance that should stay away from concentrating only in subjects with obesity. Conclusions: Our data may serve to draw the considerable attention that is currently paid to FABP4 to the adolescent population, irrespective of the presence of obesity. Further studies with larger cohorts and analyses of visceral and liver fat are warranted.