Salvage laryngectomy carries a high risk of post-operative infection with reported rates of 40-61%. The purpose of this study was to analyse infections in our own patients and review the potential impact of our current antibiotic prophylaxis (AP). A retrospective analysis of infection in 26 consecutive patients between 2000 and 2010 undergoing salvage total laryngectomy (SL) following recurrent laryngeal cancer after failed radiotherapy or chemo-radiation was undertaken. The antibiotic prophylaxis was intravenous teicoplanin, cefuroxime and metronidazole at induction and for the following 24 h. Infection was defined by Tabet and Johnson's grade 5, categorized as pharyngocutaneous fistula. Fifteen patients (58%) developed a post-operative wound infection, which occurred on average at 12 days after surgery. Univariate analysis demonstrated three risk variables that had a significant correlation with infection: alcohol consumption (p = 0.01), cN stage of tumour (p < 0.01), and pre-operative albumin levels <3.2 g/L (p = 0.012). There was a trend, though not significant, for increased infection in patients with high or low BMIs. The most common organisms isolated from clinical samples from infected patients were methicillin-resistant Staphylococcus aureus MRSA (43%), Pseudomonas aeruginosa (36%), Serratia marcescens, Proteus mirabilis and Enterococcus faecalis (7% each). All these organisms are typical hospital-acquired pathogens. Pseudomonas and Serratia were not covered by the prophylactic regime we used. The current antibiotic regime following SL is inadequate as the rate of infection is high. It would therefore seem logical to trial a separate antibiotic protocol of AP for patients undergoing SL that would include an extended course of antibiotics after the standard prophylaxis. In addition, infection rates may also be reduced by improving the metabolic state of patients pre-operatively by multi-disciplinary action. Steps should also be taken to reduce cross-infection with nosocomial pathogens in these patients. Other aspects of surgical management should be also taken in consideration.