BACKGROUND Carbon dioxide (CO2) laser resurfacing produces a superficial second-degree burn that needs to be protected from bacterial and fungal infections. OBJECTIVE We investigated the effects of various systemic and topical antimicrobial regimens. METHODS Four different regimens using oral ciprofloxacin, topical antibiotics (intranasal mupirocin ointment and otic solution), oral ketoconazole, and oral fluconazole were tested in four time periods. The frequency and types of the infections with various regimens was compared. RESULTS The study included 356 sequential patients who underwent facial CO2 laser resurfacing. Infections occurred in 27 patients (7.6%). Without antibiotic prophylaxis, 8.2% of patients had bacterial infections from days 3 to 12 after the procedure (average, day 5). With prophylactic ciprofloxacin only, 4.3% of patients had bacterial infections; these occurred almost exclusively after ciprofloxacin was discontinued. For 7 months, patients were randomly assigned to either receive or not receive mupirocin intranasally. All Staphylococcus aureus infections that occurred were seen in patients who had used intranasal mupirocin. Yeast infections were seen in 6 patients (1.7%), but mostly occurred more than 10 days after the procedure. Yeast infections were of approximately equal occurrence in the ciprofloxacin group (2.2%) and in the non-ciprofloxacin group (1.8%). No yeast infections occurred in patients who had undergone antifungal prophylaxis. CONCLUSIONS Post-CO2 resurfacing infections are not rare but can appear subtly and might only be noticeable in the second postoperative week. Prophylactic intranasal mupirocin is ineffective, but ciprofloxacin is effective in preventing infection with both gram-positive and gram-negative bacteria. Oral ketoconazole and fluconazole are effective in preventing yeast infections.