Background Oxygen is critical to the prevention of hypoxemia-induced morbidity and mortality; yet, access remains inadequate in most low- and middle-income countries despite billions of dollars spent over decades to increase supply. We present a new method for supplemental oxygen delivery whereby the OXFO System (OXFO Corporation, Boston, MA, USA) converts pressurized oxygen to ambient pressure for patient inhalation on demand at a fixed concentration across fluctuations in respiratory rate or tidal volume. This study’s primary aims were to examine the oxygen volume savings and test the non-inferiority of mean peripheral oxygen saturation (SpO2) with the OXFO System (OXFO Condition) compared to conventional continuous flow (Standard Condition) in a clinical population of oxygen-dependent hospitalized adults. Methods We conducted a non-inferiority, single-visit, randomized, crossover design. A total of 20 subjects were randomized to receive either OXFO Condition or Standard Condition first. Subjects were administered oxygen for 20 minutes during each condition after oxygen was titrated to target therapeutic SpO2. A one-sample t-test was performed to compare the mean ratio of oxygen volume dispensed (OXFO Condition/Standard Condition) with 100%. A paired t-test for non-inferiority was used to test the hypothesis that the mean SpO2 for OXFO Condition is no worse than 2.8% lower (absolute difference) than the mean SpO2 for Standard Condition. Results Nineteen subjects were included in the analyses. When considering the dispensing of oxygen as a ratio (OXFO Condition / Standard Condition) for each subject, the mean was 7.7% (standard deviation(SD)=5.4%; range=0-20%) and this was significantly different from 100% (P<0.001). The savings ratio was not significantly correlated with Standard Condition rate of flow (P=0.23). Mean SpO2 for OXFO Condition was 91.07% (SD=2.20%) and 91.35% (SD=1.62%) for Standard Condition and the difference was significantly above the non-inferiority margin of -2.80% (P<0.001). Conclusions The OXFO System saves a significant volume of oxygen while achieving non-inferior mean saturation for hospitalized oxygen-dependent patients. The OXFO System appears to maintain robust volume savings of nearly 13x across doses up to 6 liters per minute (L/min). This has significant implications for advancing equitable access to oxygen.