Background Oritavancin is a FDA-approved single-dose IV therapy for the treatment of acute bacterial skin and skin structure infections caused (or suspected to be caused) by certain Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Published data describing the outcomes of patients with skin and soft tissue infections (SSTIs) who received oritavancin beyond its pivotal phase III clinical trials are scant. Objective The purpose of this report was to describe the results of two separate multicenter observational cohort studies that described the outcomes associated with two unique real-world usage patterns of oritavancin. Methods The first cohort (n = 115) examined patients 18 years or older who were treated with oritavancin at three outpatient sites for SSTIs caused by suspected or confirmed Gram-positive pathogens, including MRSA, to avoid hospital admission. Patients were included if they had not been discharged from the inpatient setting within the previous 24 h and received their single-dose oritavancin treatment at a hospital-based outpatient infusion center. The primary outcomes measured were 30-day healthcare costs and admissions (all cause and infection related). The second cohort (n = 151) was a multicenter, retrospective chart review of adult patients who were discharged early from seven hospitals in 2015 on oritavancin for SSTIs. The primary outcome was readmission of patients within 30 days (all cause and infection related). Results In cohort 1, 30-day mean healthcare costs were USD 3698. In the study of patients who started oritavancin in the outpatient setting, 7 patients (6.1%) were admitted to hospital within 30 days of the index treatment, and 3 of those (2.6% overall) were deemed to be due to an infection. In cohort 2, all-cause and infection-related 30-day readmission rates were 6.6% and 2.6%, respectively, among patients who received oritavancin at hospital discharge. Conclusions Findings from these studies suggest that oritavancin may be a potentially useful agent to avoid hospitalization or shorten hospital length of stay among appropriate SSTI patients. Future comparator studies are required to properly ascertain the outcomes and potential benefits associated with oritavancin relative to other commonly used antibiotics in patients with SSTIs.