Objective: The beneficial effects of antiseptics in the treatment of periodontitis are still controversial. The goal of this randomized split-mouth study was to evaluate the clinical and microbiologic results of a unique subgingival irrigation of 10% povidone-iodine in addition to a full-mouth scaling and root planing for the treatment of chronic periodontitis. Method and Materials: Twenty patients with chronic periodontitis took part in this investigation. In each patient, four initially untreated pockets ≥ 4 mm were randomly selected for one subgingival irrigation. After a one-session full-mouth treatment with scaling and root planing (SRP), two pockets of a split mouth received one unique irrigation with 10 mL 0.9% NaCl solution (control group, CG). Two pockets on the other side received 10 mL of povidone-iodine 10% (test group, PIG). Full-mouth plaque score (FMPS), full-mouth bleeding score (FMBS), Plaque Index (PI), Gingival Index (GI), probing pocket depth (PPD), and clinical attachment level (CAL) parameters were assessed at baseline and after 1, 3, and 6 months (M). Bacterial samplings with sterile paper points were taken at M0 and after M1, M3, and M6. These samplings were separately cultured under aerobic and anaerobic conditions before CFU evaluation. Results: Pl, GI, PPD, and CAL were significantly improved in both groups after 6 months. The major difference was seen between M0 and M3 (P .001). No significant differences were seen between the groups, except for deep pockets (> 6 mm) where a statistical difference was observed in favor of PIG after 6 months; in these subgroups the mean probing reduction was 2.68 ± 0.37 mm for CG versus 3.93 ± 0.23 mm in PIG (P .001). No significant differences were seen between CG and PIG regarding the microbiologic results after 6 months. Conclusion: One single irrigation of 10% povidone-iodine associated with full-mouth SRP would bring a small additional benefit in deep pockets. More studies are needed to yield additional results. Keywords: chronic periodontitis, microbiology, povidone-iodine, root planing