Numerical methods for determining end-capillary gas contents for ventilation-to-perfusion ratios were first developed in the late 1960s. In the 1970s these methods were applied to validate distributions of ventilation-to-perfusion ratios measured by the multiple inert-gas-elimination technique. We combined numerical gas analysis and fluorescent-microsphere measurements of ventilation and perfusion to predict gas exchange at a resolution of similar to 2.0-cm(3) lung volume in pigs. Oxygen, carbon dioxide, and inert gas exchange were calculated in 551-845 compartments/animal before and after pulmonary embolization with 780-mu m beads. Whole lung gas exchange was estimated from the perfusion- and ventilation-weighted end-capillary gas contents. Before lung injury, no significant difference existed between microsphere-estimated arterial PO2 and PCO2 and measured values. After lung injury, the microsphere method predicted a decrease in arterial PO2 but consistently underestimated its magnitude. Correlation between predicted and measured inert gas retentions was 0.99. Overestimation of low-solubility inert gas retentions suggests underestimation of areas with low ventilation-to-perfusion ratios by microspheres after lung injury. Regional deposition of aerosolized and injected microspheres is a valid method for investigating regional gas exchange with high spatial resolution.