Introduction: Skin and soft tissue infections (SSTIs) are a common reason for presentation to an emergency department (ED). Although many patients with mild SSTI are managed with oral antibiotics, those with mild-moderate infections are often treated with parenteral antibiotics, managed in EDs as outpatients using once daily intravenous cefazolin combined with oral probenecid. 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 uncomplicated mild-moderate SSTIs patients presenting to the ED.. Methods: This was a prospective, multi-center, double dummy-blind, randomized 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, 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 step-down, admission to hospital and adverse events were also evaluated. Results: 206 patients were randomized 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 (-3.3% to 7.1%), p-value for non-inferiority=0.001). Clinical cure at seven days was not significantly different (100% and 97.7%, risk difference -2.3%, 95% CI (-4.9% to 0.3%), p-value for non-inferiority=0.008). Conclusion: Cephalexin at appropriate doses appears to be a safe and effective alternative to outpatient parenteral cefazolin and probenecid in the treatment of uncomplicated mild to moderate SSTIs who present to the ED.