Background: Laser skin resurfacing (LSR) has emerged as a popular procedure for facial rejuvenation; however, there are no clear guidelines regarding systemic antibiotic prophylaxis. Objective: We attempt to provide practical guidelines for antibiotic prophylaxis in LSR based on our experiences, pharmacology, and a review of the literature. Methods: In a pilot study, four consecutive full-face LSR patients were treated without oral or topical antibiotics. The next four patients received oral prophylaxis with a narrow spectrum antibiotic. We also report the case of a severe gram-negative infection after LSR. Results: For full-face LSR, 2 of 4 consecutive patients without antibiotic prophylaxis experienced focal Staphylococcus aureus infection. The next 4 consecutive patients, who had received gram-positive oral prophylaxis, were all culture negative after 2 days. All test sites (5 of 5) were culture negative despite the absence of systemic or topical antibiotics. One patient not in the pilot study receiving gram-positive antibiotic prophylaxis experienced a gram-negative infection. Conclusion: We recommend narrow-spectrum gram-positive oral antibiotic coverage for full-face and regional LSR. (J Am Acad Dermatol 1998;39:975-81.)