Introduction: Current guideline recommendations for optimal management of non-purulent skin and soft tissue infections (SSTIs) are based on expert consensus. There is currently a lack of evidence to guide emergency physicians on when to select oral versus intravenous antibiotic therapy. The primary objective was to identify risk factors associated with oral antibiotic treatment failure. A secondary objective was to describe the epidemiology of adult emergency department (ED) patients with non-purulent SSTIs. Methods: We performed a health records review of adults (age 18 years) with non-purulent SSTIs treated at two tertiary care EDs. Patients were excluded if they had a purulent infection or infected ulcers without surrounding cellulitis. Treatment failure was defined any of the following after a minimum of 48 hours of oral therapy: (i) hospitalization for SSTI; (ii) change in class of oral antibiotic owing to infection progression; or (iii) change to intravenous therapy owing to infection progression. Multivariable logistic regression was used to identify predictors independently associated with the primary outcome of oral antibiotic treatment failure after a minimum of 48 hours of oral therapy. Results: We enrolled 500 patients (mean age 64 years, 279 male (55.8%) and 126 (25.2%) with diabetes) and the hospital admission rate was 29.6%. The majority of patients (70.8%) received at least one intravenous antibiotic dose in the ED. Of 288 patients who had received a minimum of 48 hours of oral antibiotics, there were 85 oral antibiotic treatment failures (29.5%). Tachypnea at triage (odds ratio [OR]=6.31, 95% CI=1.80 to 22.08), chronic ulcers (OR=4.90, 95% CI=1.68 to 14.27), history of MRSA colonization or infection (OR=4.83, 95% CI=1.51 to 15.44), and cellulitis in the past 12 months (OR=2.23, 95% CI=1.01 to 4.96) were independently associated with oral antibiotic treatment failure. Conclusion: This is the first study to evaluate potential predictors of oral antibiotic treatment failure for non-purulent SSTIs in the ED. We observed a high rate of treatment failure and hospitalization. Tachypnea at triage, chronic ulcers, history of MRSA colonization or infection and cellulitis within the past year were independently associated with oral antibiotic treatment failure. Emergency physicians should consider these risk factors when deciding on oral versus intravenous antimicrobial therapy for non-purulent SSTIs being managed as outpatients.