Efficacy and Safety of 40% Urea as an Adjuvant to Antifungals for Onychomycosis: A Systematic Review and Meta‐Analysis

Onychomycosis remains a challenging condition due to varying cure rates and the risk of recurrence. Topical 40% urea has been proposed as an adjuvant to antifungals to enhance efficacy. Many trials have been done, presenting mixed results. Four databases (PubMed, Web of Science, Scopus, and EBSCO), two registers (Cochrane), and grey literature sources were used to identify randomised controlled trials (RCTs) and non-randomised studies (NRSs) published until February 2025. Cure rates (clinical, mycological, and total) were analysed in the meta-analysis, analysing cure rates and comparing urea as an adjuvant to antifungal therapy with antifungals alone. We independently selected eligible articles and extracted relevant data before assessing the quality of the studies. A summary of the findings table was made with GRADEpro GDT using the results of the meta-analyses. Based on six RCTs and six NRSs involving 424 participants treated with antifungals plus topical 40% urea-130 of which were compared to 129 participants who received antifungals without urea- we found that adding topical 40% urea as an adjuvant significantly improved the clinical cure rate compared to therapy using antifungals alone (OR: 2.05, 95% CI: 1.03-4.11, p < 0.05). However, there were no significant differences in mycological and total cure rates (OR: 1.71; 95% CI: 0.63-4.61; p > 0.25 and OR 1.23; 95% CI: 0.47-3.23; p > 0.5). The reported adverse effects were localised. Topical 40% urea can be used to improve the clinical efficacy of antifungals for onychomycosis. However, evidence for mycological and total efficacy is lacking. Thus, more rigorous trials are needed to confirm its efficacy and safety. PROSPERO-CRD42025638277.