Alveolar macrophages (AMs) and lymphocytes are activated in pulmonary sarcoidosis. Mediators from these cells are potentially important in the pathophysiology and pathogenesis of this disease. To determine whether the enhanced release of reactive oxygen species (ROS) participates in inflammatory events in sarcoidosis, and to explore the relationship between ROS release and clinical parameters, we studied ROS metabolism of AMs and other airspace cells by luminol-enhanced chemiluminescence and by direct biochemical measurement of superoxide anion production. Ten of 17 patients with sarcoidosis were prospectively found to have active disease by objective radiographic, functional, and laboratory criteria. In these subjects, ROS metabolism by AMs was significantly enhanced compared either with healthy control subjects or with patients with inactive sarcoidosis. Abnormalities in ROS metabolism were not seen in peripheral blood monocytes, suggesting that this increased metabolic activity is compartmentalized to the lung. Enhanced ROS metabolism by AMs was associated with recent adverse chest radiographic changes, recent decline in forced vital capacity, and more advanced radiographic type. These data support the hypothesis that ROS generated by airspace cells can promote parenchymal inflammation in sarcoidosis, are associated with physiologic and radiologic changes, and may thereby contribute to the pathogenesis of sarcoidosis.