Appropriate oral antibiotic therapy for the treatment of acute bacterial skin and skin structure infections (ABSSSI) is a challenge, as current oral treatment guidelines do not fully cover the most common skin pathogens. Both linezolid and omadacycline are available as intravenous or bioequivalent oral formulations. This post hoc analysis of the OASIS-1 (ClinicalTrials.gov identifier NCT02378480) and OASIS-2 (ClinicalTrials.gov identifier NCT02877927) phase 3 trials assessed safety and clinical efficacy of intravenous (IV)-start versus oral (PO)-start therapy in patients treated with omadacycline or linezolid for ABSSSI. In OASIS-1, patients were randomized to IV omadacycline or linezolid, with optional switch to oral therapy, while patients in OASIS-2 received oral omadacycline or linezolid. Treatment was provided for 7-14days in both studies. The primary endpoint was an early clinical response (ECR) at 48 to 72h, defined as survival and ≥ 20% reduction in lesion size, without rescue antibacterial therapy. A total of 645 IV-start inpatients and 735 PO-start outpatients were assessed. Median age was 47years for the IV-start group and 44years for the PO-start group. Most patients had solely gram-positive infections (97% in each group; ECR [85.2% IV-start and 85.0% PO-start]), and the incidence of treatment-emergent adverse events (AEs) was similar between the groups. The most frequent AEs observed were nausea (11.2% [IV-start] versus 18.9% [PO-start]) and subcutaneous abscess (5.6% [IV-start] versus 1.9% [PO-start]). Discontinuation due to AEs was infrequent in both groups (2% [IV-start] versus 1.2% [PO-start]). Oral therapy is equally efficacious to IV therapy when omadacycline or linezolid is used to treat ABSSSIs. These data strengthen the evidence for oral omadacycline as a therapeutic option for ABSSSI, particularly for patients who have experienced treatment failure because of the limitations of other therapies. Clinicaltrials.gov, NCT02378480 and NCT02877927.