Proton magnetic resonance (MR) imaging to quantify regional ventilation–perfusion ((Formula presented.)) ratios combines specific ventilation imaging (SVI) and separate proton density and perfusion measures into a composite map. Specific ventilation imaging exploits the paramagnetic properties of O2, which alters the local MR signal intensity, in an FIO2-dependent manner. Specific ventilation imaging data are acquired during five wash-in/wash-out cycles of breathing 21% O2 alternating with 100% O2 over ~20 min. This technique assumes that alternating FIO2 does not affect (Formula presented.) heterogeneity, but this is unproven. We tested the hypothesis that alternating FIO2 exposure increases (Formula presented.) mismatch in nine patients with abnormal pulmonary gas exchange and increased (Formula presented.) mismatch using the multiple inert gas elimination technique (MIGET).The following data were acquired (a) breathing air (baseline), (b) breathing alternating air/100% O2 during an emulated-SVI protocol (eSVI), and (c) 20 min after ambient air breathing (recovery). MIGET heterogeneity indices of shunt, deadspace, ventilation versus (Formula presented.) ratio, LogSD (Formula presented.), and perfusion versus (Formula presented.) ratio, LogSD (Formula presented.) were calculated. LogSD (Formula presented.) was not different between eSVI and baseline (1.04 ± 0.39 baseline, 1.05 ± 0.38 eSVI, p =.84); but was reduced compared to baseline during recovery (0.97 ± 0.39, p =.04). There was no significant difference in LogSD (Formula presented.) across conditions (0.81 ± 0.30 baseline, 0.79 ± 0.15 eSVI, 0.79 ± 0.20 recovery; p =.54); Deadspace was not significantly different (p =.54) but shunt showed a borderline increase during eSVI (1.0% ± 1.0 baseline, 2.6% ± 2.9 eSVI; p =.052) likely from altered hypoxic pulmonary vasoconstriction and/or absorption atelectasis. Intermittent breathing of 100% O2 does not substantially alter (Formula presented.) matching and if SVI measurements are made after perfusion measurements, any potential effects will be minimized.