The amino acid L-arginine has been administered as a single supplement to humans in an effort to improve the outcome of seriously ill patients. In normal individuals, markers of collagen biosynthesis have increased with daily oral doses ranging from 14 to 24.8 g of free arginine for 14 d. No clinical evidence of improved wound healing has been reported in the few patient studies performed to date. Administration of enteral, but not intravenous, arginine has been associated with markers of improved immune function in normal individuals and in some, but not all, patient groups studied. A single study in premature infants suggested that supplementation of L-arginine (261 mg . kg(-1) . d(-1)) administered by both the parenteral and enteral routes decreased the incidence of necrotizing enterocolitis. A single study demonstrated that oral arginine administration in conjunction with conventional chemotherapy for active tuberculosis to HIV- but not HIV+ individuals enhanced treatment responses. In both these area, larger multicenter investigations are needed. For a difference to be a difference it has to make a difference. Supplementation of only L-arginine does not to date universally show benefit, nor does it show harm. At this time there is no rationale for the routine supplementation of arginine alone to enhance recovery from serious illness. Because of the potential for harm, this amino acid should only be administered to critically ill patients in large doses under carefully monitored study conditions.