Objective: To characterize the heterogeneity in response to lifestyle intervention among Latino adolescents with obesity. Methods: We conducted secondary data analysis of 90 Latino adolescents (age 15.4 ± 0.9 y, female 56.7%) with obesity (BMI% 98.1 ± 1.5%) that were enrolled in a 3 month lifestyle intervention and were followed for a year. Covariance pattern mixture models identified response phenotypes defined by changes in insulin sensitivity as measured using a 2 hour oral glucose tolerance test. Baseline characteristics were compared across response phenotypes using one-way ANOVA and chi-square test. Results: Three distinct response phenotypes (PH1, PH2, PH3) were identified. PH1 exhibited the most robust response defined by the greatest increase in insulin sensitivity over time ([beta] ± SE, linear 0.52 ± 0.17, P < 0.001; quadratic -0.03 ± 0.01, P = 0.001). PH2 showed non-significant changes, while PH3 demonstrated modest short-term increases in insulin sensitivity which were not sustained over time (linear 0.08 ± 0.03, P = 0.002; quadratic -0.01 ± 0.002, P = 0.003). At baseline, PH3 (1.1 ± 0.4) was the most insulin resistant phenotype and exhibited the highest BMI% (98.5 ± 1.1%), 2 hours glucose concentrations (144.0 ± 27.5 mg/dL), and lowest beta-cell function as estimated by the oral disposition index (4.5 ± 2.8). Conclusion: Response to lifestyle intervention varies among Latino youth with obesity and suggests that precision approaches are warranted to meet the prevention needs of high risk youth.