Enteral feeding with formulas containing proteins as small peptides may be better tolerated and more efficacious than whole-protein diets, particularly in critically ill patients. We stratified patients beginning enteral feeding according to treatment with antibiotics or not and serum albumin level (≤25 or > 25 g/L) and randomly assigned them to treatment with a small-peptide enteral diet or a whole-protein diet. All causes of diarrhea were ascertained (defined as > 200 g stool or ≥ three liquid stools on 2 consecutive days). The study was considered complete when diarrhea occurred, or when substantial feeding had been administered without diarrhea for ≥5 days. Most of the 41 subjects who completed the trial were critically ill. Eight subjects experienced diarrhea (20%), which was caused by tube feeding in six patients (four consuming the small-peptide diet and two consuming the whole-protein diet) and by other factors in two (one on each regimen). Diarrhea was not associated with serum albumin, treatment with antibiotics, or critical illness. There were no differences between treatment groups regarding changes in serum prealbumin or fibronectin. During 5 days of feeding, a small- peptide diet and a whole-protein diet produce similar rates of diarrhea and similar changes in serum proteins.