Background: Topical efinaconazole 10% solution is a promising new treatment for distal lateral subungual onychomycosis (DLSO). However, it is unknown whether this treatment is both compatible and efficacious in individuals wearing toenail polish. Materials and Methods: We evaluated the efficacy and compatibility of efinaconazole 10% solution with concurrent nail polish use in treating DLSO over 52 weeks. Efficacy was assessed using the onychomycosis severity index (OSI) and by measuring nail growth and thickness, while compatibility with nail polish was evaluated with questionnaires. Results: Eleven patients completed the study; 6 wore nail polish regularly and 5 abstained from polish. The efficacy of efinaconazole was not diminished by concurrent nail polish use as measured by OSI, nail growth, and thickness. However, this treatment produced undesirable cosmetic changes to the quality of nail polish over time. Conclusions: While efinaconazole 10% solution is an effective treatment of DLSO in patients wearing nail polish, this treatment may diminish the quality of the polish. Further research and development is needed to enhance the compatibility of topical onychomycosis treatments with nail polish use.