Our aim was to examine the effect of acute inflammation localized in the colon and early macronutrient restriction on protein synthesis in a piglet model. In a 2 x 2 factorial design, piglets (n = 32) were fed an adequate or macronutrient-restricted diet with or without dextran sulfate-induced colitis for 7 d. The stable isotope tracer L-[5,5,5-(2)H(3)]leucine was infused to determine protein kinetics at the whole-body level and synthesis of tissue and plasma proteins. In the well-nourished state, colitis did not affect weight gain or protein kinetics except for an increase in albumin synthesis (P < 0.05). Macronutrient restriction alone caused a general slowing of protein metabolism including decreased weight gain (P < 0.0004), whole-body protein turnover (P < 0.0001), and liver (P < 0.01) and plasma protein (P < 0.03) synthesis. However, in the presence of macronutrient restriction, colitis compromised weight gain further (P < 0.02) and decreased muscle protein synthesis (P < 0.05) due to a redistribution of protein metabolism that supported enhanced synthesis of plasma proteins. The increased contribution of plasma protein synthesis to whole-body protein turnover was attributable mainly to increased synthesis of albumin (P < 0.006). Concentrations of plasma proteins were unaffected despite dramatic changes in their synthesis rates, thereby underestimating the effects of malnutrition and colitis on protein metabolism. Increased synthesis of plasma proteins, particularly the negative acute phase reactant albumin, compromises weight gain and muscle protein synthesis only when macronutrient intake is inadequate, underscoring the role of adequate nutrition in preventing growth impairment and muscle wasting in acute inflammation. These results suggest that the hypoalbuminemia of inflammatory bowel disease should not be attributed to decreased synthesis.