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The purpose of our study was to determine if cephalexin 500 mg orally four times daily was non-inferior to cefazolin 2 g intravenously daily plus probenecid 1 g orally daily in the management of patients with uncomplicated mild–moderate skin and soft tissue infection (SSTI) presenting to the ED.This was a prospective, multicentre, double dummy-blind, randomised controlled non-inferiority trial conducted at two tertiary care teaching hospitals in Canada. Patients were enrolled if they presented to the ED with an uncomplicated SSTI, and randomly assigned in a 1:1 fashion to oral cephalexin or intravenous cefazolin plus oral probenecid for up to 7 days. The primary outcome was failure of therapy at 72 hours. Clinical cure at 7 days, intravenous to oral medication transition admission to hospital and adverse events were also evaluated.206 patients were randomised with 104 patients in the cephalexin group and 102 in the cefazolin and probenecid group. The proportion of patients failing therapy at 72 hours was similar between the treatment groups (4.2% and 6.1%, risk difference 1.9%, 95% CI −3.7% to 7.6%). Clinical cure at 7 days was not significantly different (100% and 97.7%, risk difference −2.3%, 95% CI −6.7% to 0.8%).Cephalexin at appropriate doses appears to be a safe and effective alternative to outpatient parenteral cefazolin in the treatment of uncomplicated mild–moderate SSTIs who present to the ED.NCT01029782; Results.