Type II (non-insulin-dependent) diabetes mellitus is a metabolically heterogeneous condition, and is invariably preceded by impaired glucose tolerance (IGT). We examined whether metabolic heterogeneity is a feature of IGT. Three subject groups were studied: IGT subjects with two or more living non-insulin-dependent diabetic relatives (IGTWF, n = 17), and IGT subjects (IGTWOF, n = 17) and subjects with normal glucose tolerance (NGT, n = 25) without a family history of diabetes. Glucose tolerance, glucose (KITTG) and nonesterified fatty acid (KITTNEF) insulin sensitivity, and first-phase insulin secretion (FPIS) were assessed by oral glucose tolerance (OGTT), insulin tolerance (ITT), and intravenous glucose tolerance (IVGTT) tests, respectively. Comparison of groups was made by ANOVA and t test. The three groups were matched for age, gender, body mass index (BMI), and waist to hip ratio (WHR). IGTWOF and IGTWF subjects had comparable 2-hour plasma glucose levels on OGTT, and insulin secretion and KITTG were decreased to comparable degrees. However, in comparison to IGTWF subjects, IGTWOF subjects had increased fasting serum triglyceride (geometric mean, 1.8 [range, 0.8 to 4.5] v 1.1 [0.4 to 2.5] mmol. L-1, P = .02) and 2-hour plasma nonesterified fatty acid ([NEFA] mean +/- SD, 0.12 +/- 0.07 v 0.08 +/- 0.03 mmol.L-1, P < .02) levels and decreased KITTNEF values (4.0 [1.7 to 8.9] v 6.2 [2.8 to 12.1]%.min-1, P < .02). Thus, the two IGT groups had comparable changes in glucose metabolism, but IGTWOF subjects had additional abnormalities of lipid metabolism. In conclusion, metabolic heterogeneity is a feature of IGT, and this may reflect underlying etiological heterogeneity.