Purpose This study aimed at investigating the mechanisms underlying the oxygenation response to proning and recruitment maneuvers in coronavirus disease 2019 (COVID-19) pneumonia. Methods Twenty-five patients with COVID-19 pneumonia, at variable times since admission (from 1 to 3 weeks), underwent computed tomography (CT) lung scans, gas-exchange and lung-mechanics measurement in supine and prone positions at 5 cmH 2 O and during recruiting maneuver (supine, 35 cmH 2 O). Within the non-aerated tissue, we differentiated the atelectatic and consolidated tissue (recruitable and non-recruitable at 35 cmH 2 O of airway pressure). Positive/negative response to proning/recruitment was defined as increase/decrease of PaO 2 /FiO 2 . Apparent perfusion ratio was computed as venous admixture/non aerated tissue fraction. Results The average values of venous admixture and PaO 2 /FiO 2 ratio were similar in supine-5 and prone-5. However, the PaO 2 /FiO 2 changes (increasing in 65% of the patients and decreasing in 35%, from supine to prone) correlated with the balance between resolution of dorsal atelectasis and formation of ventral atelectasis ( p  = 0.002). Dorsal consolidated tissue determined this balance, being inversely related with dorsal recruitment ( p  = 0.012). From supine-5 to supine-35, the apparent perfusion ratio increased from 1.38 ± 0.71 to 2.15 ± 1.15 ( p  = 0.004) while PaO 2 /FiO 2 ratio increased in 52% and decreased in 48% of patients. Non-responders had consolidated tissue fraction of 0.27 ± 0.1 vs. 0.18 ± 0.1 in the responding cohort ( p  = 0.04). Consolidated tissue, PaCO 2 and respiratory system elastance were higher in patients assessed late (all p  < 0.05), suggesting, all together, “fibrotic-like” changes of the lung over time. Conclusion The amount of consolidated tissue was higher in patients assessed during the third week and determined the oxygenation responses following pronation and recruitment maneuvers.