The diagnostic procedure of chronic pulmonary opacities may envisage the search for non-Hodgkin lymphoma (NHL). Previous retrospective studies have shown that clonality analysis of bronchoalveolar B lymphocytes could reflect the clonality of pulmonary lymphocytes. Our objective was to define the diagnostic usefulness of bronchoalveolar lavage (BAL) B-lymphocyte clonality analysis in the setting of a clinical suspicion of both primary and secondary pulmonary lymphoma. A prospective BAL fluid B-cell clonality analysis was performed by polymerase chain reaction (PCR) in 106 consecutive patients presenting with a clinical suspicion of pulmonary NHL. Diagnosis was pulmonary B-cell lymphoma for 22 patients (13 primary and 9 secondary). When compared, pulmonary biopsy and BAL fluid have clonal identity. The detection of a strong B-cell clonal population in BAL fluid was associated with the diagnosis of pulmonary NHL (P< .0001), with a 97% specificity and a 95% negative predictive value. Thus, the absence of a dominant B-cell clone detection in BAL fluid could help to dismiss invasive investigations of pulmonary lesions. The detection of a dominant B-cell clone would lead to the performance of a pulmonary biopsy to get histologic diagnosis in primary pulmonary lymphoma and, by contrast, would avoid the need for biopsy in the setting of a secondary pulmonary lymphoma. (Blood. 2004;103: 3208-3215)