To ascertain the diagnostic reliability of transbronchial biopsy (TBB) a prospective comparison with open lung biopsy was made. All patients with undiagnosed diffuse infiltrative (interstitial) lung disease had a TBB. When this was characteristic of tumor, sarcoidosis, or infection, no additional biopsy was deemed necessary. In all other patients, an open biopsy was performed. Between January 1976 and May 1980, among 176 patients with interstitial disease, 60 (34.1%) required lung biopsy. Transbronchial biopsy was contraindicated in 7, leaving 53 in the study group. Among these 53 patients TBB was diagnostic in 20 (37.7%), and the histologic findings in the remaining 33 patients who lacked definitive tissue diagnoses were reported as normal lung, 10 patients; nonspecific abnormalities, 11 patients; interstitial pneumonia, 6; interstitial fibrosis, 3; inadequate specimen, 3. Open biopsy in these 33 patients resulted in specific diagnoses in 92%, and these diagnoses bore little relationship to the original TBB diagnoses. We concluded that TBB diagnoses of interstitial pneumonia, chronic inflammation, nonspecific reaction, and fibrosis are unreliable and often entirely misleading. In this group, an open biopsy is required to reach a specific histologic diagnosis.