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Purpose: The adjunctive subgingival application of sodium hypochlorite/amino acid and a mixture of natural and crosslinked hyaluronic acid gels (high molecular weight) has been recently proposed as a novel modality to enhance the outcomes of non-surgical periodontal therapy. The aim of this prospective case series was to evaluate the clinical outcomes obtained following the subgingival application of a combination of sodium hypochlorite/amino acid and a mixture of natural and cross-linked hyaluronic acid (high molecular) gels in conjunction with non-surgical periodontal therapy. Material and Methods: Twenty-one systemically healthy, non-smoking patients diagnosed with stage II-III, grade A/B periodontitis underwent full-mouth subgingival debridement (SD) performed with ultrasonic and hand instruments. All sites with probing depths (PD) ≥ 4mm were treated with additional repeated (i.e., 2-3 times) instillation of sodium hypochlorite/amino acid gel in the periodontal pockets prior to and during SRP. Following mechanical debridement, a mixture of natural and cross-linked hyaluronic acid (high molecular) gel was applied in the pockets. The primary outcome variable was PD reduction; changes in clinical attachment level (CAL) and bleeding on probing (BOP) were the secondary outcomes. The clinical parameters were assessed at baseline, 3 and 6 months after therapy. Results: Compared to baseline, a statistically significant mean reduction of PD values was obtained after 3 and 6 months, amounting to 2.6 ± 0.4 mm, and 2.9 ± 0.4 mm, respectively (p < 0.001). Mean CAL gain measured 2.3 ± 0.5 mm at 3 months and 2.6 ± 0.5 mm at 6 months in comparison to baseline (p < 0.001). Mean reduction of BOP values was 54.9 ± 16.9 % at 3 months and 65.6 ± 16.4 % at 6 months (p < 0.001). The number of moderate pockets (4-5 mm) decreased from 1808 at baseline to 274 at the 6-month evaluation, and the number of deep (≥ 6mm) pockets dropped from 319 to 3, respectively. Conclusion: The combination of sodium hypochlorite/amino acid and a mixture of natural and cross-linked hyaluronic acid (high molecular) adjunctive to subgingival debridement may represent a valuable approach to improve the outcomes of non-surgical periodontal treatment. [ABSTRACT FROM AUTHOR]