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Background Insulin resistance ( IR) is one of the major metabolic complications of obesity in children and adolescents. DEP domain-containing mammalian target of rapamycin interacting protein ( DEPTOR) is involved in downstream insulin signaling and DEPTOR's effects are regulated by its level of expression. Objectives To analyze promoter region of DEPTOR for genetic variants associated with altered IR in obese children and adolescents. Subjects and methods IR was determined in 322 normoglycemic obese subjects [173 females, 149 males; mean age 13.3 ± 3.5 yr, mean BMI-SDS 2.85 ± 0.83, HbA1C 5.2 ± 0.2% (33 ± 2.5 mmol/mol)] using homeostatic model assessment - insulin resistance [ HOMA-IR (>2 prepubertal and >3 pubertal)] and whole body insulin sensitivity index [ WBISI (<6.5 prepubertal and <4.5 pubertal)]. Genetic variants, determined by high resolution melting analysis, were confirmed by Sanger sequencing, whereas population allele distribution was determined by TaqMan genotyping probes. Results Genetic variant c.- 143T>C (rs7840156) was associated with a significant 2-fold decreased risk to present with IR, determined by HOMA-IR [odds ratio ( OR) = 0.614, 95% confidence interval ( CI) = 0.435-0.867, p = 0.0057) and WBISI ( OR = 0.582, 95% CI = 0.414-0.817, p = 0.0018). The CC genotype had lower mean HOMA-IR value (2.47 ± 0.44 vs. 3.04 ± 0.14, p = 0.0177) and higher mean WBISI value (7.00 ± 0.71 vs. 5.27 ± 0.33, p = 0.0235) than TT genotype. Variant c.- 143T>C was located in evolutionary highly conserved region in DEPTOR promoter region. Conclusion Presented results on association between insulin sensitivity and genetic variants in DEPTOR gene suggest DEPTOR and mammalian target of rapamycin signaling pathway to be potential target for future research and pharmacological interventions. [ABSTRACT FROM AUTHOR]