Although arginine has been shown to improve healing in rodents and in small induced wounds in healthy volunteers, little is known about the effects of arginine supplementation on healing of clinically relevant surgical wounds. We studied 18 patients in a double-blind randomized pilot study (12 men, 6 women), who underwent skin transplantation as part of reconstructive surgery. Patients were randomly assigned to receive arginine (n = 8) or placebo (n = 10) supplementation as an enteral dose of 36.2 g of l-arginine-HCl or an isocaloric amount of placebo (51.2 g alanine), respectively. Wound healing was evaluated at the donor sites of skin grafts by measuring angiogenesis, reepithelialization, and neutrophil count. Arginine metabolism was studied by measuring plasma and wound fluid amino acid concentrations. Our results show that none of these parameters were significantly different between the oral arginine supplementation group and the placebo group. In conclusion, enteral arginine supplementation does not improve wound healing of skin donor sites.