OBJECTIVE: This study was designed to reflect real-world experience in the treatment of patients with AMS. Efficacy, safety, and patient-reported outcomes variables were compared between moxifloxacin (MXF) and amoxicillin/clavulanate (AC) for the management of AMS in a primary care setting. METHODS: In this prospective, multicenter, non-blinded phase IIIb trial, 475 adult patients with symptoms of AMS were randomized to receive a 10-day oral regimen of either MXF (400mg once-daily) or AC (875mg twice-daily). Clinical success at the test-of-cure (TOC) visit (post-therapy days 14-21) was the primary efficacy measure. Secondary outcomes included rate of clinical relapse at follow-up (post-therapy days 26-46) and exploratory evaluation of patient-reported outcomes variables. Safety data was also tabulated from intent-to-treat (ITT) patients. RESULTS: Of 471 adults comprising the ITT population (234 MXF, 237 AC), MXF treatment was statistically equivalent to AC at the TOC visit (85.2% vs 81.8%; 95%CI=-6%,13%). Per-protocol analysis also confirmed statistical equivalence between MXF and AC (86.5% vs 83.6%; 95%CI=-7%,13%). Rates of relapse were similar for the ITT (4% MXF, 5% AC) and the per-protocol (4% both) populations. The frequency of drug-related adverse events were similar between MXF (30%) and AC (25%) and were primarily gastrointestinal-related: nausea (11% MXF, 5% AC) and diarrhea (3% MXF, 10% AC). At the TOC visit, significantly more MXF-treated patients (n=47; 24%) in the ITT population than AC -treated patients (n=28; 14%) reported symptomatic improvement by day 3 (p <0.02). No differences existed in terms of lost work hours or time to return to normal activities between treatment groups. CONCLUSIONS: In this primary care clinical trial, once-daily MXF was as effective and safe as twice-daily AC in the treatment of AMS. In some patients, MXF was associated with more rapid symptomatic relief, which has potential clinical and socioeconomic implications.