We studied the effects of left lower lobe (LLL) alveolar hypoxia on ventilation-perfusion (VA/Q) heterogeneity in anesthetized dogs with acute (1-h-old) and mature (24-h-old) permeability pulmonary edema, induced by intravenous administration of 0.05 ml/kg of oleic acid. The left upper lobe was removed and a bronchial divider was placed to allow separate ventilation of the right lung (fraction of inspired oxygen [FIO2] = 1.0) and the LLL (FIO2 = 1.0 or 0.05). Gas exchange was assessed using the multiple inert gas elimination technique. In acute pulmonary edema, LLL hypoxia reduced LLL blood flow and increased true shunt of the LLL compared with a hyperoxic control group. VA/Q heterogeneity of the LLL was markedly increased, indicated by increases in the logarithmic standard deviation of the perfusion distribution (log SDQ) and the retention index of dispersion corrected for shunt (DISPR*). Increases in true shunt and log SDQ were significantly greater than those observed with lobar hypoxia in normal lungs before oleic acid injury. In mature oleic acid injury, LLL alveolar hypoxia resulted in a similar reduction in LLL blood flow and increase in inert gas shunt and DISPR*. We conclude that lobar alveolar hypoxia increased VA/Q heterogeneity of the hypoxic lobe to a greater degree in oleic acid-induced pulmonary edema compared with normal lungs. Phase of oleic acid injury (acute versus mature) did not affect gas exchange during alveolar hypoxia.