Muscle exchange of amino acids (AAs) was evaluated by using the arteriovenous-difference technique across the leg in seven patients with chronic renal failure (CRF) and eight control subjects before and for 75 min after the ingestion of an AA mixture simulating an animal-protein meal. Total AAs increased in arterial blood much more in patients with CRF after AA ingestion than in control subjects, as a consequence of an exaggerated increase in nonessential AAs (NEAAs) (+127%). Moreover, total AAs were taken up by the leg in larger amounts than in control subjects (+71%, P < 0.0025) because of increased uptake of NEAAs (+156%, P < 0.005). Branched-chain AA uptake by the leg was, in absolute values, similar to that of control subjects; however, because of the increased uptake of total AAs, branched-chain AA uptake was only 30% of total AA extraction, compared with 46% in control subjects. Abnormalities in AA uptake by muscle paralleled those in arterial AAs. In fact the same AAs that increased abnormally in blood were taken up by the leg at higher rates than in control subjects. Variations in arterial concentrations and muscle uptake of AAs were inversely related to arterial bicarbonate concentration, suggesting a role for acid-base status in modifying both the arterial supply and muscle metabolism of AAs. Results indicate that in CRF patients the normal pattern of postprandial AA repletion is disrupted. Muscle tissue faces the increased and unbalanced postprandial supply of AAs with an augmented and unbalanced uptake. Data are consistent with an abnormal use of exogenous AAs in CRF patients, possibly induced by metabolic acidosis.