Purpose: The aim of this study was to report the successful clinical outcome of recalcitrant neurotrophic keratopathy (NK) treated with insulin eye drops associated with therapeutic Hyper-CL soft contact lens (CL) (EyeYon Medical, Ness Ziona, Israel)., Methods: This study is a case report., Results: A 40-year-old man was referred to our clinic for the management of severe recalcitrant NK developed after surgical and adjuvant radiotherapy treatment of adenoid cystic carcinoma of the nasal cavity with basicranial involvement. The patient presented with severe conjunctival hyperemia, a large (7 × 4 mm) central epithelial defect, corneal opacity and thinning, and deep corneal neovascularization. Unpreserved tear substitutes, vitamin A ointment, punctal plug, bandage CL, and autologous serum had been used for the previous 3 months without success. Patient was prescribed insulin eye drops (1 unit per mL), and therapeutic Hyper-CL soft CL was applied to increase the contact time between insulin eye drops and the corneal surface. Follow-up visits were performed at day 10 (T1) and day 20 (T2). A marked reduction in the epithelial defect size was noted at T1 and complete healing was reached at T2. Simultaneously, conjunctival hyperemia and corneal opacity markedly reduced over time with treatment., Conclusions: The combination of insulin eye drops and therapeutic Hyper-CL soft CL was effective in determining healing of recalcitrant NK not responsive to standard treatments and bandage CL. It is unclear whether the positive outcomes were determined by insulin eye drops, Hyper-CL, or the combination of both, and future randomized clinical trials are warranted to determine the contribution of each treatment., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)