It was suggested by analysis of theoretical lung models that low V/Q units are unstable and can be converted into shunt by breathing O2. We tested this theory in 21 subjects with various lung diseases (mostly chronic obstructive pulmonary disease) by having them breathe O2. We also increased the tidal volumes in these patients to see whether this maneuver could prevent the development of shunt. We found that mean P(A-a)O2 increased from 30 ± 2.8 (mean ± SEM) Torr breathing room air to 135 ± 20.7 Torr breathing O2 for 10 min (p < 0.0001), to 124 ± 20.4 Torr breathing O2 for 20 min (p < 0.0001), and to 125 ± 19.0 Torr breathing oxygen with inspiratory capacity breaths (p < 0.0001). The corresponding shunt increased from about 2.8% of the cardiac output to 7.9 ± 1.01, 7.3 ± 1.03 and 7.3 ± 0.98%, respectively. We conclude that: (1) breathing pure oxygen can convert low V/Q units to shunt, hence measurement of P(A-a)O2 and shunt by oxygen technique will overestimate the actual values; (2) 10 min of oxygen breathing will cause complete atelectasis of low V/Q units, and (3) increased tidal volume does not prevent absorptive atel