1. By using ion-exchange columns coupled to a sensitive automated Sakaguchi reaction, in addition to the normal ninhydrin reaction for amino acids, homoarginine, a guanidino homologue of arginine, was found in the plasma and urine of both normal and cystinuric individuals.
2. In all seven cystinuric subjects studied, urinary excretion of homoarginine was approximately ten times that found in normal subjects; the plasma levels of this amino acid were considerably reduced relative to normal individuals.
3. Homoarginine in the plasma can be derived either metabolically from lysine or from dietary sources.
4. In normal subjects homoarginine was cleared at a higher rate than arginine. On the other hand, the clearance of arginine exceeded that for homoarginine in the majority of cystinuric subjects although the values obtained for homoarginine indicate that the defect in amino acid transport also affects this amino acid.
5. The defect in the proximal tubular reabsorption of homoarginine is less severe than that for arginine, suggesting that the reabsorptive site for homoarginine may not be the same as that for arginine.
6. In the design of models for the tubular reabsorption of amino acids in health and disease, the presence of homoarginine and its excessive loss in cystinuria must be accounted for.