Free fatty acid (FFA) mobilization during fasting was measured in cats fed a meat diet (63% protein, 18% fat, 6% carbohydrate, w/w) or a carbohydrate-rich diet (15% protein, 10% fat, 70% carbohydrate), and in rats adapted to a high-protein, carbohydrate-free synthetic diet (70% casein, 8% fat) or a balanced synthetic diet (66% carbohydrate, 17% casein, 8% fat). 2. Fasted cats and rats on the high-protein diet showed reduced rates of plasma FFA increase. Their blood glucose was unchanged but higher than that of controls fed a carbohydrate-rich diet after fasting for 24 (rats) or 48 h (cats). 3. The steady-state rate of plasma FFA replacement was determined with 1-[14C]-palmitate in fed and fasted rats with plasma FFA levels ranging from 0.30 to 1.45 mumol/ml adapted to the high-protein or to the balanced diet. Under these dietary conditions, the FFA replacement rates were linearly related to the concentration of plasma FFA. However, the slope of the regression line was steeper for the rats on the high-protein diet. Thus, for the same concentration of plasma FFA, replacement rates for rats adapted to the high-protein diet were higher than for controls. 4. These data indicate that the higher rates of FFA replacement required in situations demanding an increased supply of FFA for animals on high-protein regimens are attained with smaller increases in plasma FFA concentration.