Introduction: Emergency department (ED) patients with non-purulent skin and soft tissue infections (SSTIs) requiring intravenous antibiotics may be managed via outpatient parenteral antibiotic therapy (OPAT). To date, there are no prospective studies describing the performance of an ED-to-OPAT clinic program. Furthermore, there are no studies that have examined physician rationale for intravenous therapy, despite this being a critical first step in the decision to refer to an OPAT program. Methods: We conducted a prospective observational cohort study of adults (age 18 years) with non-purulent SSTIs receiving parenteral therapy at two tertiary care EDs. Patients were excluded if they had purulent infections or could not provide consent. The emergency physician completed a form documenting rationale for intravenous therapy, infection size, and choice of antimicrobial agent, dose and duration. OPAT treatment failure was defined as hospitalization after a minimum of 48 hours of OPAT for: (i) worsening infection; (ii) peripheral intravenous line complications; or (iii) adverse antibiotic events. Patient satisfaction was assessed at a 14-day telephone follow up. Results: We enrolled a consecutive sample of 153 patients (mean age 60 years, 82 male (53.6%) and 38 (24.8%) with diabetes). A total of 137 patients (89.5%) attended their clinic appointment. Of the 101 patients prescribed cefazolin, 50.5% received 1000 mg and 48.5% received 2000 mg per day. There were low rates of OPAT treatment failure (3.9%). None of the adverse peripheral intravenous line events (9.8%) or adverse antibiotic events (7.2%) required hospitalization. Patients reported a high degree of satisfaction with timeliness of clinic referral (median score 9 out of 10) and overall care received (median score of 10 out of 10). The top 5 reasons given by physicians for selecting intravenous therapy were: clinical impression of severity (52.9%); failed oral antibiotic therapy (41.8%); diabetes (17.6%); severe pain (7.8%); and peripheral vascular disease (7.8%). Conclusion: This is the first study to identify physician rationale for the use of intravenous antibiotics for SSTIs. There was significant variability in antibiotic prescribing practices by ED physicians. This prospective study demonstrates that an ED-to-OPAT clinic program for non-purulent SSTIs is safe, has a low rate of treatment failures and results in high patient satisfaction.