OBJECTIVE: The study aimed to identify wound sites/procedures where infection incidence was over 5%, such that these circumstances may warrant wound infection antibiotic prophylaxis. METHOD: We undertook a 3-year prospective study of 5,091 lesions (predominantly nonmelanoma skin cancer) treated on 2,424 patients from July 2002 to June 2005. No patient was given prophylactic antibiotics, and no patient ceased warfarin or aspirin. RESULTS: Overall infection incidence was 1.47%. Individual procedures had the following infection incidence: curettage 0.73% (3/412); skin flap repairs 2.94% (47/1601); simple excision and closure 0.54% (16/2974); skin grafts 8.70% (6/69); and wedge excision 8.57% (3/35). Analysis of regions of the body demonstrated that surgery below the knee (n=448) had an infection incidence of 6.92% (31/448) (p<.0001). Subanalysis demonstrated that all regions below the knee were at high infection risk. Elsewhere, groin excisional surgery had an infection incidence of 10% (1/10) (p=.027). No other body site demonstrated an infection incidence beyond 5% of statistical significance. Procedures on the face demonstrated an infection incidence of 0.81% (18/2,209). Diabetic patients, those on warfarin and/or aspirin, and smokers showed no difference in infection incidence. CONCLUSION: Based on a prediction of infection incidence over 5%, the following cutaneous oncologic procedures warrant consideration of oral antibiotic wound infection prophylaxis: all procedures below the knee, wedge excisions of lip and ear, all skin grafts, and lesions in the groin. Other than under these circumstances, surgery to the nose, ear, fingers, lips, skin flap surgery, and surgery on diabetics, smokers, and those on anticoagulants have previously been considered for wound infection prophylaxis but do not warrant such intervention based on our data.