We studied the acquisition of methicillin-resistant Staphylococcus aureus (MRSA) in two groups of patients who had free flap reconstructions of defects after excision of lesions in the head and neck. The first group ( n = 31) was given a 5-day perioperative course of antibiotic prophylaxis (long-term) and the second ( n = 33) a 24-h course (short-term). MRSA was the main infecting organism. Seventeen of the 64 patients (27%) developed an infection with MRSA, including seven at donor sites of free flaps. All infections were acquired after operation, and delayed healing or discharge in five patients with MRSA and four with infections with other organisms. The median length of hospital admission was greater for patients that acquired MRSA ( p = 0.005). There were significantly fewer patients with wounds infected by MRSA in the short-term group (4/33 compared with 13/31, p = 0.01). We recommend the short-term use of an antibiotic for surgical prophylaxis and the application of cross-infection control measures on the ward.