Lipid and protein ingested before carbohydrate reduce postprandial hyperglycemia. We tested feasibility, safety and clinical efficacy of manipulating the sequence of nutrient ingestion in patients with type 2 diabetes (T2D). After a 4-week run-in, 17 T2D patients were randomized to either a control diet (CD) or to an experimental diet (ED) allowing the consumption of high-carbohydrate foods only after high-protein and high-fat foods at each main meal (lunch+dinner). Both diets were accurately followed and neutral on arterial blood pressure, plasma lipids and indices of hepatic and kidney function. After 8 weeks, in spite of a similar reduction of body weight (ED -1.9 95% confidence interval (-3.4/-0.4)kg, P<0.03; CD -2.0 (-3.6/-0.5)kg, P<0.02) and waist circumference (ED -2.9 (-4.3/-1.5)cm, P<0.002; CD -3.3 (-5.9/-0.7)cm, P<0.02), the ED only was associated with significant reductions of HbA1c (-0.3 (-0.50/-0.02)%, P<0.04), fasting plasma glucose (-1.0 (-1.8/-0.3)mmol l(-1), P<0.01), postprandial glucose excursions (lunch -1.8 (-3.2/-0.4)mmol l(-1), P<0.01; dinner: -1.0 (-1.9/-0.1)mmol l(-1), P<0.04) and other indices of glucose variability (s.d.: -0.5 (-0.7/-0.2)mmol l(-1), P<0.02; Coefficient of variation: -6.6 (-10.4/-2.7)%, P<0.02). When compared with the CD, the ED was associated with lower post-lunch glucose excursions (P<0.02) and lower glucose coefficients of variation (P<0.05). Manipulating the sequence of nutrient ingestion might reveal a rapid, feasible, economic and safe strategy for optimizing glucose control in T2D.