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 (lipoprotein) A-I and LpA-I:A-II. 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 HDL-C 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.