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Background: Major LLA remains a common operation in the United Kingdom with ⁓5000 procedures performed yearly. Amputations are described as ‘clean surgery’ and SSIs in this patient cohort have been previously under-reported. The true incidence lies between 13-35% and is associated with patient mortality, morbidity and implications on health economics. Previous work done in this thesis has demonstrated lack of consensus in clinical practice regarding perioperative antibiotic prophylaxis, and lack of high quality studies to formulate and sustain a common practice across the UK. Methods: A single centre RCT was designed to which a total of 161 patients were recruited and randomised to receive either a 5-day or a 24-hour prophylactic antibiotic course. Within the groups further allocation to skin preparation (alcoholic chlorhexidine Vs. alcoholic povidone iodine) was performed by stratification. Results: A total of 153 patients were included in the final analysis. Groups were well matched for comorbidities and demographics. The use of a 5-day course was associated with a statistically significant lower incidence of SSI(n=9, 11.5%) when compared to the 24-hour group (n=27, 36%) (P < 0.001) and lower incidence of IWH(n=20, 25.6% Vs. n=40, 53.3% respectively) (P < 0.001). History of diabetes, smoking, and transmetatarsal amputations performed, were statistically significant independent factors associated with an increase in SSI incidence (P=0.018, P=0.005, and P<0.001 respectively). Choice of skin preparation between alcoholic chlorhexidine and povidone iodine had no effect on the incidence of SSI/IWH (P=0.851 and P=0.326 respectively). The presence of SSI statistically significantly increased the post-operative length of hospital stay (from median 14 to 28 days, P=0.015) Conclusions: This is a Level 1 study which demonstrated that the use of a 5-day over a 24-hour antibiotic course can significantly reduce incidence and risk of SSI/IWH development. It has also highlighted 3 independent factors, 2 of which could be addressed during the preoperative optimisation stage to reduce the risk of developing an SSI post-operatively. The presence of SSI is associated with prolonged hospital stay, something which has significant implications on patient morbidity as well as incurring significant costs on healthcare resources.