Transbronchial biopsy (TBB) is widely used after lung transplant but may not be diagnostic. Our group has used invasive approaches, open lung biopsy (OLB) or video-assisted thoracoscopy (VAT), to establish a definitive diagnosis in unexplained clinical deterioration. We sought to demonstrate the risks and benefits of this approach.A retrospective review was made of the case notes of the patients undergoing OLB or VAT during a 12-year period from August 1996.During a 12-year period in 442 recipients, there were 51 invasive biopsies in 45 patients (6 had 2 procedures), of which 41 (80%) were OLB and 10 (20%) were VAT. Time of biopsy ranged from 7 days to 11 years after transplant. Thirty-seven (73%) took place in the first year, including 12 (24%) within the first 30 days. Nine patients died within 30 days of biopsy; 7 of them were already ventilated. Overall, biopsy provided a new unsuspected diagnosis in 37% of patients and confirmed the diagnostic suspicion in 47%. In only 16% of patients did it fail to provide a result that was clinically useful. The results of 29 (57%) biopsies led to a change in treatment. Sixty-three percent of new diagnoses and 71% where clinical suspicion was confirmed resulted in a treatment change. In all but 2 cases, a change was made to medication.In this large series of invasive biopsies, there was a high rate of useful results, with a frequent change in treatment. Invasive biopsies are a safe intervention in ambulatory patients.