A mixture of polynucleotides and hyaluronic acid (PN-HA) has shown several modulating effects in the healing process. This study aimed to assess the safety and clinical performance of PN-HA alone or in association with deproteinized bovine bone mineral (DBBM) with papillary preservation flap (PPFs) in the treatment of residual pockets. A total of 43 patients with 55 infrabony defects were recruited; 30% were smokers. The mean baseline probing depth (PD) was 7.7 ± 1.9 mm with a corresponding mean recession (Rec) of 1.9 ± 1.3 mm. The infrabony defect depth at the surgical measurement was 5.2 ± 2.1 mm. DBBM was applied at 56% of the defects, as they were determined to be noncontained defects based on clinical judgment. Healing was uneventful at all sites. After 1 year, PD reduction was 4.4 ± 1.8 mm, with a Rec increase of 1.0 ± 0.8 mm. The radiographic bone fill was 3.5 ±1.9 mm. The multilevel analysis showed that an absence of smoking habits was associated with improved PD reduction (P = .026) and bone gain (P = .039). PN-HA mixture is a safe product for periodontal surgery and seems to promote clinical benefits in the treatment of residual pockets associated with infrabony defects.