Objectives: In the present pilot, multicenter, randomized, single-blinded, controlled study, surgical treatment with or without the administration of D-PLEX₅₀₀ (a biodegradable prolonged release local doxycycline formulated with β-tricalcium phosphate bone graft) was accessed for the treatment of peri-implantitis. Method and materials: Subjects undergoing surgical treatment for intrabony peri-implantitis defects after flap elevation were randomly assigned, to adjunct D-PLEX₅₀₀ placement group or to control group. Clinical and radiographic parameters were measured at 6 and 12 months. Results: Twenty-seven subjects (average age: 64.81 ± 7.61 years) were enrolled; 14 patients (18 implants) were randomized to the test group and 13 (14 implants) to the control group. There was no difference in plaque scores between the groups. There was no difference in the changes of mean periodontal probing depth between the test and control groups between baseline and the 6-month follow-up, whereas statistically significant difference was observed after 12 months' follow-up when analyzed for all sites averaged. There was a statistically significant difference in the changes of clinical attachment levels and radiographic bone levels between the groups between baseline and 12 months. These improvements were demonstrated when analyzed at both implant and subject levels. Only D-PLEX₅₀₀ treatment led to improved bone levels at both time points. The improvement in bone levels was significant in the D-PLEX₅₀₀ treatment group already after 6 months, and further improved over the 12-month follow-up. Implants were lost only in the control group (14%). Conclusions: D-PLEX₅₀₀ sustained release local antibiotic formulated with bone filler showed promising results in enabling healing of peri-implantitis lesions. The antibacterial component of the bone graft material might create favorable conditions that enable implant surface decontamination and soft and hard tissue healing over a prolonged period. Keywords: bacteria, bone augmentation, dental implants, periodontitis, plaque