PURPOSE: To study the long-term anatomic and physiologic effects of nocturnal normobaric hyperoxia (NNBH) in a patient with treatment-resistant diabetic macular edema (DME). METHODS: A 64-year-old diabetic man with bilateral DME requiring regular anti-VEGF treatments in both eyes was started on 5 LPM (40% FiO2) NNBH treatment 6-h per night. Visual acuity, OCT measurements of retinal thickness and volume, as well as the number of injections given in each eye were retrospectively examined one year prior and prospectively after initiation of NNBH, as well as before and after a planned 1-month discontinuation of NNBH. RESULTS: The patient received 12 anti-VEGF injections in the year prior to beginning NNBH treatment (4 OD; 8 OS) and did not require any injections after commencing NNBH treatment. Visual acuity improved and stabilized to 20/20 and macular edema rapidly resolved in both eyes following initiation of NNBH. After a planned 1-month NNBH vacation, DME recurred but quickly resolved once NNBH treatment was restarted. CONCLUSION: This model case demonstrates that a 6-h NNBH regimen can be successful in treating DME and improving vision, without the need for intravitreal injections. NNBH is a more acceptable treatment regimen compared to 24-h continuous oxygen delivery and may provide a less invasive alternate method for treating DME in patients with diabetes. Further study is warranted.