Background: Diets that provoke less insulin secretion may be helpful in the prevention and management of diabetes. A physiologic basis for ranking foods according to insulin "demand" could therefore assist further research. Objective: We assessed the utility of a food insulin index (FII) that was based on testing isoenergetic portions of single foods (1000 kJ) in predicting the insulin demand evoked by composite meals. Design: Healthy subjects (n = 10 or 11 for each meal) consumed 13 different isoenergetic (2000 kJ) mixed meals of varying macronutrient content. Insulin demand predicted by the FII of the component foods or by carbohydrate counting and glycemic load was compared with observed insulin responses. Results: Observed insulin responses (area under the curve relative to white bread: 100) varied over a 3-fold range (from 35 ± 5 to 116 ± 26) and were strongly correlated with insulin demand predicted by the FII of the component foods (r = 0.78, P = 0.0016). The calculated glycemic load (r = 0.68, P = 0.01) but not the carbohydrate content of the meals (r = 0.53, P = 0.064) also predicted insulin demand. Conclusions: The relative insulin demand evoked by mixed meals is best predicted by a physiologic index based on actual insulin responses to isoenergetic portions of single foods. In the context of composite meals of similar energy value, but varying macronutrient content, carbohydrate counting was of limited value.