We report the clinical and histologic findings of lung biopsies from 48 patients with pulmonary Langerhans cell granulomatosis (PLCG) and show how special techniques such as immunohistochemistry, electron microscopy (EM), and high resolution computerized tomography (HRCT) of the lungs can be useful in diagnostically challenging cases. Nineteen patients were men and 29 were women. The median age was 33 years (range 15-54 years). Two had pituitary involvement. Bone lesions were observed in four patients and biopsy proven in two. All patients were cigarette smokers. In six patients HRCT revealed a combination of thin-walled cystic and nodular lesions. The pathologic diagnosis was established on the basis of open lung biopsy specimens in 44 cases and transbronchial biopsy specimens in 4 of 10 cases. In two transbronchial biopsies, diagnostic PLCG infiltrates were seen in toluidine blue-stained thick sections in the tissue processed for EM but not on the tissue processed for histology. EM in both of these cases revealed Birbeck granules within LCs. The diagnosis was supported by a positive bone biopsy in one of these patients and characteristic HRCT findings in the other. The antibody to S100 protein stained the LC infiltrates in the five cases studied. This staining and the characteristic findings on HRCT confirmed the diagnosis in one case in which the PLCG lesions were obscured by atelectasis. The frequent finding of intraluminal fibrosis (78% of open lung biopsies) supports the recent suggestion that this alteration plays an important role in the pathogenesis of fibrotic remodeling in PLCG. The strong association of PLCG with cigarette smoking and the frequent peribronchiolar location of PLCG lesions (87% of open lung biopsies) in our cases are consistent with the concept that in adults this disorder is associated with an abnormal response to cigarette smoke.