We studied the effects of enteral supplements on protein and energy intakes, body composition, energy expenditure, and gastrointestinal histology in 49 subjects with human immunodeficiency virus--associated weight loss (12.7 ± 0.9% of body wt). We also determined whether a stable--isotope mass spectrometric measurement at baseline might predict the short-term response of fat-free mass (FFM) measured by bioelectrical impedance analysis. Thirty-nine subjects completed the study after being randomly assigned to receive either a whole--protein--based (n = 22) or a peptide--based (n = 17) formula. A non-supplemented, nonrandomly assigned group (n = 13) was followed concurrently. Both formulas were well tolerated. Voluntary intakes of energy and protein from nonsupplement sources decreased significantly during supplementation [by 819--1638 kJ (196--382 kcal)/d and 5.6--14.4 g protein/d, respectively; P<0.01] but to a lesser extent than the intake from the supplement [2300--2510 kJ (550--600 kcal)/d and 19--28 g protein/d, respectively], so that net increases in intakes of protein and energy (P < 0.03), as well as of several vitamins and trace elements were increased. Nevertheless, the mean FFM did not increase for the group as a whole, although there was considerable interindividual heterogeneity. Changes in FFM at 6 wk were significantly inversely correlated (r = 0.65, P < 0.01) with baseline synthesis of fat (de novo hepatic lipogenesis), but not with other potential measures of energy intake (insulin-like growth factor 1 or its binding protein) or inflammation (soluble tumor necrosis factor receptors I or II). The prospective identification of FFM response by measurement of de novo hepatic lipogenesis supported the hypothesis that the subset of wasting patients whose FFM is unresponsive to nutrient supplementation have altered nutrient metabolism.