Background <p>Eradication treatment of methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) carriers is an effective strategy to reduce transmission and infection rates. However, throat carriage is associated with treatment failure, and the optimal treatment for these patients remains uncertain. This study evaluated the effectiveness of topical eradication treatment in a cohort of patients with throat carriage and identified risk factors for treatment failure.</p> Methods <p>This population-based cohort study included residents of the North Denmark Region with first-time MRSA throat carriage between January 1, 2017, and December 31, 2020. Exclusions included patients under two years of age, those with occupational livestock exposure, and patients receiving systemic antimicrobial treatment. Successful eradication was defined as being MRSA-free six months after one or two topical treatment courses. Multivariable analysis assessed risk factors for treatment failure, including selected patient, environmental, and strain-related factors.</p> Results <p>Of 319 MRSA throat carriers, 258 completed the follow-up test six month after treatment. Among patients who completed follow-up, the overall eradication success rate was 43.4%. Throat carriers without additional risk factors for treatment failure achieved a 54.7% success rate, while those with additional risk factors had success rates ranging from 28.6% to 55.6%, depending on specific risk factors. Throat carriage combined with younger age, colonization by non-CC398 MRSA strains, and having MRSA-positive household members were associated with treatment failure.</p> Conclusions <p>Initial topical treatment may be appropriate for MRSA throat carriers without additional risk factors, with over half achieving long-term eradication. This approach is especially relevant given the potential adverse effects of systemic antibiotics.</p>