To assess the validity of computer-assisted methods in analyzing the lung parenchyma imaged with high-resolution computed tomography (HRCT), we compared computer-derived estimates of lung density to other, more traditional, measures of parenchymal injury in 24 subjects with idiopathic pulmonary fibrosis (IPF) and 60 subjects with extensive occupational exposure to asbestos. Gray scale density histograms were constructed from the HRCT images. The gray scale histogram of both study groups was of a skewed unimodal distribution. However, compared with the asbestos-exposed subjects, the patients with IPF had a gray scale distribution that was significantly shifted to the right (greater density) and flatter. In a multivariate analysis, after controlling for age and cigarette smoking, we found that the mean and median gray scale densities were independently associated with the presence of moderate-to-severe dyspnea, a higher International Labour Office chest X-ray category, a lower forced vital capacity, and a higher concentration of macrophages and eosinophils in the bronchoalveolar lavage fluid. These factors accounted for > 70% of the variance of the mean and median gray scale densities. Interestingly, no differences in gray scale density measures were noted between patients with IPF and patients with asbestosis when these other factors were taken into account. Our results suggest that computer-derived density analysis of the lung parenchyma on the HRCT scan is a valid, clinically meaningful, and objective measure of interstitial lung disease.