Background: Onychomycosis, a fungal nail infection, can impact quality of life. Objective: We sought to evaluate the efficacy and safety of tavaborole topical solution, 5% for treatment of toenail onychomycosis. Methods: In 2 phase-III trials, adults with distal subungual onychomycosis affecting 20% to 60% of a target great toenail were randomized 2:1 to tavaborole or vehicle once daily for 48 weeks. The primary end point was complete cure of the target great toenail (completely clear nail with negative mycology) at week 52. Secondary end points included completely or almost clear nail, negative mycology, completely or almost clear nail plus negative mycology, and safety. Results: Rates of negative mycology (31.1%-35.9% vs 7.2%-12.2%) and complete cure (6.5% and 9.1% vs 0.5% and 1.5%) significantly favored tavaborole versus vehicle (P ≤.001). Completely or almost clear nail rates also significantly favored tavaborole versus vehicle (26.1%-27.5% vs 9.3%-14.6%; P <.001). Rates of completely or almost clear nail plus negative mycology (15.3%-17.9% vs 1.5%-3.9%) were significantly greater for tavaborole versus vehicle (P <.001). Application-site reactions with tavaborole included exfoliation (2.7%), erythema (1.6%), and dermatitis (1.3%). Limitations: Duration of follow-up is a limitation. Conclusion: Tavaborole demonstrates a favorable benefit-risk profile in treatment of toenail onychomycosis.