Objective: In this prospective case series, the effects of flapless intentional replantation (IR) with root surface conditioning with enamel matrix derivative (EMD) was evaluated for the treatment of periodontally-endodontally involved hopeless teeth. Method and Materials: A total of 17 teeth (17 patients, aged 40 to 73) with ≥ 10 mm attachment loss and radiographic bone loss to the apex were included in the study. The affected teeth were atraumatically extracted using a flapless approach, then granulation tissues, calculus, and necrotic cementum on the root surfaces were removed. EMD was applied for 5 minutes to the root surfaces. The teeth were reinserted to the socket without any bone grafts and splinted. Results: After 2 years, clinical healing was uneventful in 16 cases and the radiographs revealed no root resorption or ankylosis. IR with EMD treatment provided statistically significant reduction in probing depth (6.4 ± 2.6 mm), gain in clinical attachment level (5.9 ± 2.5 mm), and gain in radiographic bone level (48.2 ± 26.1%) compared to baseline values (P .01). Conclusion: Within the limitations of the study, flapless IR with EMD treatment appeared to act as an alternative strategy to extraction of severely compromised teeth with endodontic-periodontal lesions beyond the root apex. Keywords: enamel matrix derivative, endodontic-periodontal relations, periodontal regeneration, periodontal surgery, replantation