Abstract This clinical trial compared the efficacy of doxycycline (DOX) in β-cyclodextrin (DOX)/βCD) with DOX- alone in gel on thirty-three subjects with periodontitis. Patients were randomized to group 1 GI; 10% DOX + scaling and root planning (SRP); group 2 (GII (10% DOX /β-CD + SRP), and group 3 (GIII; SRP). Gels were applied in GI and GII at baseline (T0) and 30 days later (T1). Periodontal Probing Depth (PPD), Clinical Attachment Level (CAL), Bleeding on Probing (BOP) and Visible Plaque Index (VPI) were evaluated at (T0), 30 days (T1) and 60 days after T0 (T2). Bone density was analyzed after 18 months (T3). GII showed the most significant reduction of PPD (2.62 mm; p <0.003), and greatest gain in CAL (2.54 mm p <0.003) at T2. BOP and the VPI had a strong reduction in all groups at T2 (p <0.05), both decreased by ≥5 times and 2 times, respectively, in all groups at T1. Bone density increased in all groups in radiographs (T3). The use of DOX encapsulated in β-CD gel with SRP resulted in significant improvements in clinical periodontal parameters; such molecular inclusion of doxycycline into β-CD in gel for local application is relatively simple and useful in dentistry.