To further assess the clinical significance of asbestos-induced pleural fibrosis, we performed cardiopulmonary exercise testing in 90 subjects who were exposed to asbestos. Of the 82 subjects without an abnormal resperate exercise, 35 had normal pleura, 33 had circumscribed pleural plaques, and 14 had diffuse pleural thickening. Interstitial fibrosis (International Labor Organization [ILO]. > or = 1/10) was present in 14 of 35 subjects with normal pleura, 13 of 33 subjects with circumscribed pleural plaques, and 2 of 14 subjects with diffuse pleural thickening. Although pleural fibrosis did not appear to be related to impaired respiratory function with exercise in our entire cohort, this finding was confounded by a higher proportion of interstitial fibrosis in subjects with normal pleura. In fact, among study subjects without asbestosis, significant decreases in gas exchange (higher VD/VT and increased alveolar-arterial oxygen pressure difference) were observed at maximal exercise among subjects with pleural fibrosis. Interestingly, neither a higher respiratory rate nor a lower VT/FVC ratio was observed among those with pleural fibrosis, suggesting that the mechanical effects of pleural fibrosis on the chest wall do not explain the increased VD/VT. Using multivariate analyses to control for potential confounders, regression models showed that pleural plaques (p = 0.04) and diffuse pleural thickening (p = 0.03) were independently associated with significant increases in dead space ventilation (VD/VT) with maximal exercise. These findings indicate that asbestos-induced pleural fibrosis is independently associated with decrements in gas exchange with maximal exercise and suggest that interstitial lung disease, not detected on the routine chest x-ray film, may be responsible for this abnormal response to exercise.