Objective. The purpose of this investigation was to compare the homeostasis model assessment of insulin resistance (HOMA-IR) to more direct measures of insulin action before and after lifestyle interventions in obese Latino youth. Study design. Eleven obese Latino boys (age 15.1 ± 1.6 years, body mass index (BMI) percentile 97.3 ± 3.5%) and twenty obese Latina girls (age 14.7 ± 1.8 years, BMI percentile 96.6 ± 3.6%) participated in two distinct lifestyle interventions. Boys participated in a 16-week exercise intervention and girls participated in a 12-week nutrition education program. Insulin sensitivity was determined by the frequently sampled intravenous glucose tolerance test (FSIVGTT) in boys and by a 3-hour oral glucose tolerance test with multiple sampling calculations for the whole-body insulin sensitivity index (WBISI) in girls. HOMA-IR was measured for both groups. Results. HOMA-IR was correlated at baseline to the FSIVGTT (r = −0.57, p = 0.07) and the WBISI (r = −0.78, p<0.01) and at follow-up (FSIVGTT: r = −0.81, p<0.003; WBISI: r = −0.71, p = 0.001). Post-intervention, insulin sensitivity increased 45% in the boys and 34% in the girls; however, these improvements were not reflected by significant changes in HOMA-IR. Conclusions. Improvements in insulin sensitivity following an intervention measured either by the FSIVGTT or an OGTT were not detected by HOMA-IR. Researchers and clinicians should exercise caution in relying on fasting indices, such as HOMA-IR, to determine the impact of lifestyle interventions on insulin sensitivity in overweight youth.