To evaluate the diagnostic yield (DY) of transbronchial lung biopsies (TBBs), as the relationship between the DY and the number of tissue specimens taken per TBB, we reviewed the histological and clinical data of 530 consecutive TBBs performed in 516 immunocompetent patients, having either a chronic diffuse lung infiltrate, a localized peripheral lung lesion or hilar adenopathies. The DY (positive TBBs/performed TBBs) varied significantly according to the radiographic pattern and the underlying disease. For chronic diffuse pulmonary infiltrates (n = 244), the overall DY was 50%, but higher figures were obtained for hypersensitivity pneumonitis (92%), sarcoidosis stage II-III (75%), lymphangitic carcinomatosis (68%) and pneumoconiosis (54%). The DY was lower in diffuse tuberculosis (38%) and interstitial pulmonary fibrosis (27%). For localized peripheral lung lesions (n = 205), the overall DY was only 29%, while for sarcoidosis stage I it was 56% (n = 63). Data analysis shows that there is a direct correlation between the number of samples obtained per TBB and the overall DY (i.e. 38% with one to three tissue fragments versus 69% with six to 10, p < 0.01). The increment itself depends on the radiographic pattern and/or the underlying disease which indicates that the probability of diagnostic confirmation per individual tissue sample is not always the same. The clinical implication of these findings is that whereas for some pulmonary diseases the DY is already good with few samples, more samples are to be taken to warrant a satisfactory overall DY. Accordingly, we recommend that at least five to six specimens per TBB should be taken. This number should allow a quite good overall DY in patients with diffuse lung infiltrate. On theoretical grounds, more specimens (seven to 10) should be taken for an optimal DY of localized peripheral lung lesions and of sarcoidosis at stage I. In these indications the clinician should therefore compare the risk-benefit of TBB with a high number of biopsies to the results of other diagnostic procedures.