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OBJECTIVE: Clinical heterogeneity in youth-onset type 2 diabetes is less understood than that of adult-onset type 2 diabetes. We performed phenotypic clustering of youth-onset type 2 diabetes to determine whether clusters provided clinical utility.RESEARCH DESIGN AND METHODS: We performed data-driven clustering in a diverse subset of autoantibody-negative, clinician-diagnosed type 2 diabetes before age 20 years in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) (n = 525) and the SEARCH for Diabetes in Youth (SEARCH) (n = 333) studies. Participants were clustered using 1) similar variables as previously described in adults and 2) novel routinely available clinical variables. We assessed the effectiveness of the clusters, as well as that of simple clinical measures, to predict treatment response in the TODAY clinical trial.RESULTS: There were three youth-onset type 2 diabetes clusters: 1) youth-onset insulin-deficient diabetes (YIDD-T2), 2) youth-onset insulin-resistant diabetes, and 3) intermediate youth-onset diabetes. These clusters had differential responses to therapies and risk of treatment failure in the TODAY study, with those in the YIDD-T2 cluster experiencing the highest rate of treatment failure, regardless of treatment arm. YIDD-T2 also had high rates of type 2 diabetes complications. We then generated three novel clusters, with different rates of treatment failure, using variables available in routine clinical practice. Compared with both clustering methods, simple clinical measures performed comparably or better at predicting treatment response and complications.CONCLUSIONS: Youth-onset type 2 diabetes can be characterized into reproducible clusters that demonstrate differential response to treatments and risk of complications. Nevertheless, cluster membership did not add clinical utility beyond simple clinical measures for predicting outcomes.