OBJECTIVE: To determine the prevalence of abnormal glucose homeostasis and cardiovascular risk factors in youth with acanthosis nigricans (AN). STUDY DESIGN: Youth (8-14 years) were recruited from community pediatric offices. Each subject underwent a questionnaire, a targeted physical examination, and an oral glucose tolerance test. RESULTS: Subjects (n = 236) with AN of the neck (AN+) (60% Hispanic, 30% African American, 54% female, body mass index [BMI] z-score 2.3 kg/m(2)) and 51 youth without AN (65% Hispanic, 22% African American, 37% female, BMI z-score 2.1 kg/m(2)) completed the study. Twenty-nine percent of the AN+ group had abnormal glucose homeostasis, 27% had systolic blood pressure > 95th percentile, and 50% had high-density lipoprotein-cholesterol < or =5th percentile. Once corrected for sex, puberty, maternal education, and BMI z-score, AN remained significantly associated with insulin resistance and abnormal glucose homeostasis. For youth in the AN+ group, homeostasis model assessment of insulin resistance, female sex, and positive glutamic acid decarboxylase antibodies remained significantly and independently associated with impaired glucose tolerance. CONCLUSIONS: Youth in the AN+ group had severe insulin resistance, and more than 1 in 4 already had abnormal glucose homeostasis. AN identified a high-risk population, for whom appropriate interventions have the potential to attenuate or even prevent the development of diabetes and further metabolic abnormalities.