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Amoxicillin-Clavulanate vs Amoxicillin for Acute Sinusitis in Adults. IMPORTANCE: Acute sinusitis has the highest rate of antibiotic prescribing in adults younger than 65 years. There is no consensus regarding whether amoxicillin-clavulanate or amoxicillin should be first-line treatment for uncomplicated acute sinusitis in adults. OBJECTIVE: To compare the risk of treatment failure and adverse events between standard-dose amoxicillin-clavulanate vs standard-dose amoxicillin for acute sinusitis in adults. DESIGN, SETTING, AND PARTICIPANTS: New-user, active comparator retrospective cohort study using a nationwide health care utilization database comparing amoxicillin-clavulanate vs amoxicillin for adults aged 18 to 64 years with outpatient acute sinusitis. Patients with a new acute sinusitis diagnosis between January 1, 2018, and December 1, 2023, were eligible. Statistical analysis was conducted between July and November 2025. Propensity score matching was used to help mitigate confounding. EXPOSURES: Standard-dose amoxicillin-clavulanate (875 mg-125 mg twice daily) or standard-dose amoxicillin (875 mg twice daily or 500 mg 3 times daily). MAIN OUTCOMES AND MEASURES: The primary outcome was treatment failure, defined as the first occurrence of a new antibiotic dispensation (with or without an outpatient visit), emergency department or inpatient encounter for acute sinusitis, or inpatient encounter for a sinusitis complication assessed 1 to 14 days after treatment initiation. Antibiotic-associated adverse events and secondary infections were also assessed. RESULTS: The full cohort included 521 244 eligible patients. After propensity score matching, there were 234 608 patients (117 304 patients per group; 65.5% female; median [IQR] age, 43 [31-54] years). Treatment failure occurred in 3.1% of patients overall, with 0.03% requiring an emergency department or inpatient encounter. There was no observed difference in the risk of treatment failure between the amoxicillin-clavulanate vs amoxicillin groups (3.0% vs 3.1%; risk ratio [RR], 0.96 [95% CI, 0.92-1.01]), which was consistent across sensitivity analyses. There was no difference in antibiotic-associated adverse events (1.3% vs 1.2%; RR, 1.04 [95% CI, 0.97-1.12]). The risk of secondary infections was higher for amoxicillin-clavulanate vs amoxicillin, including yeast infections (1.1% vs 0.8%; RR, 1.40 [95% CI, 1.29-1.53]) and Clostridioides difficile infections (0.04% vs 0.02%; RR, 2.14 [95% CI, 1.29-3.54]). CONCLUSIONS AND RELEVANCE: In this observational study of patients aged 18 to 64 years with acute sinusitis treated in the outpatient setting with standard-dose amoxicillin-clavulanate or standard-dose amoxicillin, there was no observed difference in treatment failure. Amoxicillin-clavulanate was associated with a higher, albeit rare, risk of adverse events. These findings suggest standard-dose amoxicillin may be a preferred first-line treatment for adults with uncomplicated acute sinusitis.