Background: The disease burden onychomycosis is not trivial. The aim is to develop a quality of life instrument to measure the onychomycosis burden. Methods: 402 patients with mycologically-confirmed onychomycosis completed a baseline questionnaire of 39 quality of life items (modified Skindex-29 questions and 10 additional nail-specific questions). Internal consistency, reproducibility and responsiveness of the final instrument, NailQoL were measured. Results: 15 items consisting of symptom (3), emotion (10), and functional (2) domains were retained in NailQoL. Symptom and emotion subscales = 0.80-0.92. Administration α demonstrated good internal consistency (Cronbach's of the instrument to 46 patients at one month after baseline revealed good reproducibility (ICC 0.88-0.91). Responsiveness was measured in 292 patients at 18 months; statistically significant better NailQoL scores were found in individuals with complete cure (mycological and clinical) (P < 0.01). Conclusion: NailQoL represents a new concise, valid, reliable, and responsive instrument for measuring burden of skin disease for patients with onychomycosis.