Background The mechanisms underlying oxygenation improvement after prone positioning in COVID-19 acute respiratory distress syndrome have not been fully elucidated yet. The authors hypothesized that the oxygenation increase with prone positioning is secondary to the improvement of ventilation-perfusion matching. Methods In a series of consecutive intubated COVID-19 acute respiratory distress syndrome patients receiving volume-controlled ventilation, the authors prospectively assessed the percent variation of ventilation-perfusion matching by electrical impedance tomography before and 90 min after the first cycle of prone positioning (primary endpoint). The authors also assessed changes in the distribution and homogeneity of lung ventilation and perfusion, lung overdistention and collapse, respiratory system compliance, driving pressure, optimal positive end-expiratory pressure, as assessed by electrical impedance tomography, and the ratio of partial pressure to fraction of inspired oxygen (Pao 2/Fio 2; secondary endpoints). Data are reported as medians [25th to 75th] or percentages. Results The authors enrolled 30 consecutive patients, all analyzed without missing data. Compared to the supine position, prone positioning overall improved ventilation-perfusion matching from 58% [43 to 69%] to 68% [56 to 75%] (P = 0.042), with a median difference of 8.0% (95% CI, 0.1 to 16.0%). Dorsal ventilation increased from 39% [31 to 43%] to 52% [44 to 62%] (P < 0.001), while dorsal perfusion did not significantly vary. Prone positioning also reduced lung overdistension from 9% [4 to 11%] to 4% [2 to 6%] (P = 0.025), while it did not significantly affect ventilation and perfusion homogeneity, lung collapse, static respiratory system compliance, driving pressure, and optimal positive end-expiratory pressure. Pao 2/Fio 2 overall improved from 141 [104 to 182] mmHg to 235 [164 to 267] mmHg (P = 0.019). However, 9 (30%) patients were nonresponders, experiencing an increase in Pao 2/Fio 2 less than 20% with respect to baseline. Conclusions In COVID-19 acute respiratory distress syndrome patients, prone positioning overall produced an early increase in ventilation-perfusion matching and dorsal ventilation. These effects were, however, heterogeneous among patients. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New