Native Americans are predisposed to insulin resistance and associated cardiovascular risk. Therefore, we studied whether BMI (body mass index) in a population of Cherokee children and adolescents is associated with HDL-C (HDL cholesterol)-, and the HDL particles Lp (lipopro-tein) A-I and LpA-I:A-I. Subjects were grouped by BMI Z score quartiles within three gender-specific age brackets (5-9, 10-14, and 15-19 y) to examine for trends in lipoprotein and HOMA-IR (homeostasis index insulin resistance) values associated with adiposity and age. HDL-C decreased by BMI Z score quartiles in all three age groups for both genders. HDL-C, LpA-I, and LpA-I:A-II decreased with age in boys but not girls. Log HOMA-IR increased by BMI Z score quartiles in all three age groups for both genders. Linear regression modeling showed BMI Z score, triglyceride, and age to be associated with HDL-C, whereas HOMA-IR was associated with LpA-I:A-II but not with HDLC or LpA-I.When waist circumference was substituted for BMI Z score in the same models, it was associated with HDL-C and both lipoprotein particles. In conclusion, adiposity is more associated with HDL-C lowering than with declines in the lipoprotein particles. HOMA-IR is less associated with HDL-C but may selectively influence LpA-I:A-II. Greater decreases in HDL-C, LpA-I, and LpA-I:A-II with age in boys is attributed to gender-specific hormonal changes. The early onset of HDL lowering in these Native American children and adolescents, particularly boys, warrants intervention strategies to prevent obesity and associated cardiovascular risk. Native Americans are predisposed to insulin resistance and associated cardiovascular risk. Thus, we studied whether BMI (body mass index) in a population of Cherokee children and adolescents is associated with HDL-C (HDL cholesterol) -, and the HDL particles Lp -tein) AI and LpA-I: AI. Subjects were grouped by BMI Z score quartiles within three gender-specific age brackets (5-9, 10-14, and 15-19 y) to examine for trends in lipoprotein and HOMA- HDL-C decreased by BMI Z score quartiles in all three age groups for both genders. HDL-C, LpA-I, and LpA-I: A-II decreased with age in boys but not girls. Log HOMA-IR increased by BMI Z score quartiles in all three age groups for both genders. Linear regression modeling showed BMI Z score, triglyceride, and age to be associated with HDL-C, whereas HOMA-IR was associated with LpA-I: A-II but not with HDLC or LpA-I.When waist circumference was substituted for BMI Z score in the same models, it was associated with HDL-C and both lipoprotein particles. In conclusion, adiposity is more associated with HDL-C lower than with declines in the lipoprotein particles. HOMA-IR is less associated with HDL- A decrease in HDL-C, LpA-I, and LpA-I: A-II with age in boys is attributed to gender-specific hormonal changes. The early onset of HDL lowering in these Native American children and adolescents, particularly boys, warrants intervention strategies to prevent obesity and associated cardiovascular risk.