The purpose of this case report is to describe a case of continuous wear of a gas-permeable mini-scleral contact lens with a fluid reservoir of autologous serum (AS) combined with AS drops as a successful empirical and accessible alternative therapeutic option for refractory persistent epithelial defects in a patient with severe neurotrophic keratopathy (NK) due to severe dry eye disease and chronic contact lens wear. A 61-year-old Caucasian female with bilateral NK presented a history of multiple episodes of bilateral persistent epithelial defects, having already been submitted to three tectonic-penetrating keratoplasties in her left eye (OS). In May 2017, the patient developedde novorefractory central neurotrophic ulcers in both eyes (OU), unresponsive to conventional treatment with preservative-free lubricants, topical antibiotics, topical anti-inflammatory agents, and oral doxycycline. By March 2018, after initiating hourly AS eyedrops, the ulcer in her right eye (OD) improved to a smaller ulcer, while her OS presented complete graft re-epithelialization. In May 2018, her OD neurotrophic ulcer was complicated with fungal and subsequent bacterial secondary infection. Eventually, a therapeutic penetrant keratoplasty was required for her OD. Subsequently, her OD graft developed ade novo6x6mm central persistent epithelial defect unresponsive to all the aforementioned therapeutic strategies. After months of unsuccessful treatment, a new therapeutic option was experimented with: a gas-permeable mini-scleral contact lens in combination with AS eyedrops. After two weeks of this treatment regimen, the corneal epithelium eventually started to regenerate, and four weeks later, the cornea was completely re-epithelized. To date, there are no signs of recurrence of the corneal epithelial defect/ulcer.