In lysinuric protein intolerance (LPI), intestinal absorption and renal tubular reabsorption of arginine, ornithine, and lysine are impaired due to a defective cationic amino acid transporter. Deficiency of arginine and ornithine restricts the function of the urea cycle, leading to hyperammonemia after protein load, and to strong protein aversion. Mealtime supplements of citrulline, another urea cycle intermediate that uses other transport mechanisms, prevent postprandial hyperammonemia and improve protein tolerance. Deficiency of lysine, an essential amino acid, most probably also contributes to the symptoms of LPI. We investigated possibilities to improve the availability of lysine for tissues by increasing plasma lysine concentration. Six patients with LPI were started on short-term oral lysine supplementation that was administered with their regular citrulline doses and standard low-protein meals. L-Lysine in consecutive doses of 0.55 and 1.1 mmol/kg caused profuse diarrhea in first 3 patients. To avoid gastrointestinal side effects, the 3 other patients were started on smaller lysine supplements of only 0.05 mmol/kg per dose, given 3 times daily for 3 days. All pre- and postprandial plasma lysine concentrations remained within normal range in 2 of the 3 patients studied. Even after the larger doses, no significant effects on the urea cycle were seen. We conclude that low-dose oral lysine supplementation normalizes plasma lysine concentration in patients with LPI, and is safe and well tolerated at least in short-term use.