To examine the relationship between morphologic changes and the alteration of pulmonary function, papain solution was administered to 11 dogs by inhalation and to 5 dogs by a single intratracheal injection. Pulmonary function tests, including determination of lung volume subdivision, diffusion capacity (DLCO), pressure-volume relationship of the lung and arterial blood gas were performed before and after papain treatment. The dogs were then killed and the lungs processed for pathologic studies. The severity of emphysema was graded as percent of emphysema according to Dunill's method and we compared this to the antemortem pulmonary function data. Exponential constant K was determined by fitting lung pressure-volume data to the equation V = Vo (1-e-KP). After papain administration, DLCO decreased, K of the pressure-volume curve increased, and arterial blood oxygen pressure reduced significantly. The changes of residual volume, the ratio of residual volume to total lung capacity, DLCO per unit lung volume, and the values of the exponential functions of pressure-volume data were correlated with the severity of emphysema with statistical significance, but none of them showed excellent order correlation. Multiple regression equation using 2 to 4 of the parameters indicated that the severity of emphysema can be predicted more accurately. We conclude that recognition of the severity of emphysema requires a multivariate approach including the determination of lung volume, DLCO, and pressure volume relationship of the lung, because the relationship between the severity of emphysema and the values obtained with these measurements are nonlinear.