Polyvinylpyrrolidone/vinyl acetate (PVP/VA) is a molecule with increased adhesion capacity, and can be associated in the bacterial plaque control with sodium DNA, a natural anti-aging molecule able to improve gingival trophism. The aim of the study is to test at two weeks the antimicrobial and antiplaque properties, subjects affected by chronic periodontitis, showed by a mouthwash containing Chlorhexidine (CHX) 0.2% with Anti Discoloration System (ADS), PVP-VA, and Sodium DNA in comparison with a placebo mouthwash. A single center randomized controlled trial was conducted on a total of fifty-four (54) subjects. In the test Group (n = 27) patients were treated by a 0.2% Chlorhexidine (CHX) mouthwash with ADS, PVP-VA, and Sodium DNA, while a placebo mouthwash was used in the control Group (B). The full mouth plaque score (FMPS), full mouth bleeding score (FMBS), and gingival index (GI) were assessed at baseline, and at 1 and 2 weeks after treatment. FMPS score recorded at baseline (V2) was 52.7 ± 9.2 in the Group Test and 58.2 ± 6.1 in the Group Control (p > 0.05). After 1 week (V3), FMPS was 13.3 ± 5.6 in the Group Test and 18.7 ± 4.3 in the Group Control (p < 0.05), while at V4 (2 weeks), FMPS was 14.2 ± 4.1 in the Group Test and 20.3 ± 5.2 in the Group Control (p < 0.05). FMBS score recorded at baseline (V2) was 46.7 ± 8.7 in the Group Test and 49.2 ± 6.2 in the Group Control (p > 0.05). After 1 week (V3), FMBS was 12.7 ± 4.2 in the test Group Test and 18.5 ± 5.9 in the control Group Control (p < 0.05), while after 2 weeks (V4), it was 13.1 ± 3.2 in the Group Test and 19.8 ± 4.9 Group Control (p < 0.05). This trial has clinically showed the efficacy of a new formulation of chlorhexidine mouthwash in reducing bacterial plaque and gingival inflammation. A significant reduction of inflammation and bleeding scores was found in periodontal patients treated by a mouthwash containing CHX 0.2% with ADS, PVP-VA, and Sodium DNA compared to those treated with a placebo mouthwash.