Skin autograft is the most important definitive treatment for acute-deep burns. Wound infection is the most important cause of autograft loss. Prior clinical studies have not shown any significant difference in the autograft survival rate and the use of perioperative systemic antibiotics. Their study assesses the potential benefit of systemic antibiotics in this setting, especially when topical antibiotics or artificial skin products are not readily available. The authors designed a prospective, randomized study in a cohort of patients with acute burns to assess the hypothesis that the use of systemic antibiotic prophylaxis affects the rate of skin autograft survival. Enrolled patients could have more than one autograft procedure done. These patients were randomized for each surgical procedure. The outcome measurement was autograft survival rate between the two groups. From October 2001 to October 2006, 77 patients were enrolled with a mean age of 41.7 years (SD +/- 19.4) and a mean skin total burn body surface area of 21.8 (SD +/- 23). The experimental group had 44 autograft procedures with systemic antibiotics (AP) and the control group had 46 procedures without antibiotics (NP). The rate of autograft survival for the AP group was 97% and for the NP group was 87% (P < .01) There was a partial autograft loss in 10 procedures (23%) in the AP group and 23 procedures (50%) in the NP group (P < .01). Patients with acute deep burns treated with autografts may benefit from systemic perioperative antibiotics prophylaxis, as antibiotics seem to be associated with increase autograft survival rate. The risk of colonization in other parts of the body with multidrug resistant bacteria warrants further study.