Moderate exposures to hyperoxia are becoming increasingly common in clinical medicine as advancing technology allows O2 to be more effectively delivered to nonintubated patients. The sensitivity of the lung to injury by a subchronic exposure to 60% O2 was investigated, using baboons and serial lobar biopsies. Because results obtained from different regions of the lung were compared, the alveolar architecture of different lung lobes of three controls was studied, with the use of electron microscopic morphometric analyses, to assess possible lobar differences in volume, surface, and numerical densities of cells and tissues. In animals exposed to 60% O2, the same techniques were used to assess specific tissue changes in the epithelial, interstitial, and endothelial compartments of the alveolar septa. All six lobes of the normal baboon lung were found to be identical with respect to alveolar architecture. Thus, for gases of low reactivity and given in high concentrations, such as O2, cross-comparisons between different lobes are appropriate. Exposure to 60% O2 was found to cause proliferation of alveolar type II epithelium, suggesting a low-grade, chronic epithelial injury. Animals allowed to recover for 8 wk in room air showed progressive changes in the alveolar interstitium, involving increases in both cells and matrix. Because sequential lobar resections were done, animals were exposed both to 60% O2 and to the effects of general anesthesia and thoracotomies. The exposure to 60% O2 for 2 wk in this experimental setting leads to an alveolar septal injury that includes a progressive interstitial fibrotic response.