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Backgrounds: Surgical site infections (SSIs) represent one of the most common and potentially preventable sources of morbidity and healthcare cost escalation associated with skin cancer surgery. There is a lack of data reporting organisms cultured from SSIs in skin surgery, with guidelines for antibiotic prophylaxis based on common skin pathogens rather than actual cultured organisms. In this study, we sought to define the cultured microbiology of SSIs specific to skin cancer surgery and test these against empiric treatment guidelines., Methods: All consenting patients presenting to the Auckland regional skin cancer treatment centre over a 6-month period were included. Patients receiving any form of antibiotics within a week prior to surgery were excluded. All wounds were assessed postoperatively, with clinically significant infections identified as those with a standardized wound infection score of 4 (range 0-7) and/or prescribed post-operative antibiotics within 3 weeks of surgery. Wound cultures were recorded., Results: About 104 clinically significant SSIs were identified from 333 lesions treated, with cultures available in 27%. Cultured organisms included MSSA (79%), MRSA (14%), coagulase-negative Staphylococci (11%), and 'skin flora' (14%). Empiric guidelines inaccurately predicted effective treatment in 14% of cases, exclusively due to MRSA., Conclusion: To our knowledge this is the first comprehensive report of SSI microbiology following skin cancer surgery. The overwhelmingly predominant organisms were Staphylococcus sp. (76%), with the rate of MRSA approaching prevalence warranting empiric first-line treatment. These data help inform effective rationalized empiric antibiotic treatment, when indicated, for optimal outcome following skin surgery., (© 2022 Royal Australasian College of Surgeons.)