Progressive systemic sclerosis (PSS) is a generalized disorder characterized by fibrosis of many organs including the lung parenchyma. Unlike most other interstitial disorders, traditional concepts of the interstitial lung disease associated with PSS have held it to be a 'pure' fibrotic disorder without a significant inflammatory component. To directly evaluate whether an active alveolitis is associated with this disorder, patients with chronic interstitial lung disease and PSS were studied by open lung biopsy, gallium-67 scanning, and bronchoalveolar lavage. Histologic evaluation of the biopsies demonstrated that the interstitial fibrosis of PSS is clearly associated with the presence of macrophages, lymphocytes, and polymorphonuclear leukocytes, both in the interstitium and on the alveolar epithelial surface. Gallium-67 scans were positive in 77% of the patients, showing diffuse, primarily lower zone uptake, suggestive of active inflammation. Consistent with the histologic findings, bronchoalveolar lavage studies demonstrated a mild increase in the proportions of neutrophils and eosinophils with occasional increased numbers of lymphocytes. Importantly, alveolar macrophages from patients with PSS showed increased release of fibronectin and alveolar-macrophage-derived growth factor, mediators that together stimulate lung fibroblasts to proliferate, thus suggesting at least one mechanism modulating the lung fibrosis of these patients. Thus, evidence from several different points of view together demonstrates that the interstitial lung disease associated with PSS is associated with chronic inflammation in the local milieu, leading to the hypothesis that the inflammation plays some role in the derangements to the alveolar structures that characterize this disorder. However, while this suggests a potential vulnerable site for therapy of this disorder, corticosteroids had no consistent effect on the gallium-67 scan or proportions of neutrophils and eosinophils in lavage fluid of these patients. Thus, while the interstitial lung disease associated with PSS is characterized by an alveolitis, the traditional therapy of interstitial lung disease does not suppress at least some components of this inflammation.