SummaryTwenty patients with large endodontic lesions, which failed to respond to conventional endodontic therapy, were selected for this study. The lesions had a radiographic diameter of at least 10 mm, were removed by periradicular surgery, before retrofilling the apices with either super EBA or dessicated zinc oxide‐eugenol. In 10 test sites large e‐PTFE membranes (Gortex) were placed to cover the lesions, while at the control sites the lesions were not covered before resuturing. Radiographic analysis of the lesions at 3, 6, 9 and 12 months revealed that lesions covered with the membranes healed quicker than the control lesions, and that the quality and quantity of the regenerted bone was superior when membranes were used. Results of the study indicate that guided tissue regeneration (GTR) principles can be effectively applied to the healing of large periapical lesions, especially in through‐and‐through