To define the clinical and metabolic characteristics of children with non-insulin-dependent diabetes mellitus (NIDDM), we reviewed the medical records of 18 children and adolescents who met either or both of the following criteria for the diagnosis of the disease: evidence of continued endogenous secretion of insulin beyond that expected in insulin-dependent diabetes mellitus and satisfactory glycemic control with diet alone or in combination with an oral hypoglycemic agent more than 2 years from the time of diagnosis. Patients who met these criteria but had islet cell antibodies or insulin autoantibodies were eliminated from the study group. Patients with NIDDM constituted 8% of all patients with diabetes seen in our pediatric clinics and 19% of diabetic patients of Central or South American ancestry. Of the 18 patients, 12 (67%) were Mexican American. The mean age of onset was 12.8 years (range, 5 to 17). Obesity (n = 9) and acanthosis nigricans (n = 12) were common findings. Ketonuria was present at diagnosis in 5 (33%) of 15 patients and acidosis in 2 of 14 (14%). Challenge with a nutritional supplement (Sustacal, Mead Johnson Nutritionals) (n = 10) showed a mean fasting serum C-peptide concentration of 1.19 nmol per liter (3.6 ng per ml). A family history of NIDDM was present in 13 (87%) of 15 patients, with 7 (47%) having 3 or more generations affected. Children with NIDDM are an important subset of those with diabetes, and this disease should be suspected in diabetic children presenting without ketoacidosis and with acanthosis nigricans, obesity, and a strong family history, particularly among those of Mexican-American ethnicity. Children with these characteristics should undergo testing of endogenous insulin secretion for appropriate therapeutic intervention.