Background 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. Methods A retrospective review was made of the case notes of the patients undergoing OLB or VAT during a 12-year period from August 1996. Results 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. Conclusions 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.