Toenail onychomycosis is a chronic fungal infection that often requires prolonged treatment in order to effectively manage pathogenic organisms and obtain a clear nail. Traditionally, certain clinical features of onychomycosis, including the presence of substantial lateral disease, focal fungal masses, yellow/brown streaks, and extensive nail involvement (ie, >50%), indicate a poor treatment prognosis and have proven difficult-to-treat with oral or traditional topical therapies. Owing to the novel features of topical tavaborole, we sought to understand the potential utility of tavaborole in difficult-to-treat onychomycosis. A blinded, post-hoc assessment of Phase III trials was conducted, focusing on initial presentation, midpoint assessment (24 weeks), and final outcomes (52 weeks) in subjects identified as having difficult-to-treat onychomycosis and treated for 48 weeks with once-daily application of either tavaborole 5% solution or vehicle. Our post-hoc analysis identified 84 difficult-to-treat cases (tavaborole 5%; n=60; vehicle, n=24) in subjects with toenail onychomycosis due to Trichophyton rubrum or Trichophyton mentagrophytes. No subjects identified as difficult-to-treat and treated with vehicle achieved a complete cure, while 6 subjects treated with tavaborole 5% attained a completely clear nail and negative mycology. Similarly, 7 subjects treated with tavaborole 5% solution achieved an almost complete cure (≤10% involvement and negative mycology) while 1 subject on vehicle achieved an almost complete cure. We present a case series of 4 patients, of varying age and difficult-to-treat clinical features, which responded positively to tavaborole 5% solution. Three of the subjects achieved complete cure after being treated with tavaborole 5%, with one additional subject (an 88-year-old female) achieving an almost complete clear nail by treatment end. The outcomes presented here may not be reflective of patients that may present with these clinical characteristics. Additional investigations would be useful in order to assess the value of topical tavaborole 5% solution in difficult-to-treat clinical presentations of onychomycosis. <p><em>J Drugs Dermatol. 2017;16(10):1016-1021.</em></p>.