OBJECTIVE Povidone-iodine [polyvinylpyrrolidone-iodine complex (PVP-iodine)] might constitute a valuable adjunct to current periodontal therapy because of its broad-spectrum antimicrobial activity, low potential for developing resistance and adverse reactions, wide availability, ease of use, and low financial cost. This investigation employed a randomized, split-mouth study design to determine the microbiological and clinical effects of 10% PVP-iodine subgingival irrigation in periodontitis lesions showing radiographic evidence of subgingival calculus. METHODS Sixteen adults having at least one periodontal pocket of 6 mm or more in each quadrant of the dentition and harboring one or more periodontopathic bacteria participated in the study. In each subject, a study site in each quadrant was randomly chosen to receive either subgingival irrigation with 10% PVP-iodine together with scaling and root planing, scaling and root planing alone, subgingival irrigation with 10% PVP-iodine, or subgingival irrigation with sterile saline. Prior to therapy and at 5 weeks post-treatment, microbiological culture was carried out without knowledge of the clinical status or the type of treatment rendered. A blinded clinical examiner determined presence of dental plaque, probing pocket depth, and gingival bleeding on probing. Microbiological and clinical data were analyzed using a repeated measures analysis of variance and Kruskal-Wallis rank test with the Tukey and Mann-Whitney post hoc tests. RESULTS At 5 weeks post-treatment, subgingival irrigation with PVP-iodine together with scaling and root planing caused a 95% or greater reduction in total pathogen counts in 44% of pockets having >/= 6 mm depth whereas scaling and root planing alone, povidone-iodine irrigation alone and water irrigation alone caused 95% reduction of total pathogens only in 6-13% of similar study sites (P = 0.02). Reduction in mean pocket depth was 1.8 mm for the PVP-iodine/scaling and root planing group, 1.6 mm for the scaling and root planing group, and 0.9 mm for the PVP-iodine and the saline monotherapy groups, with statistical significance reached for the scaling and root planing group vs. the PVP-iodine group (P = 0.04) and for the scaling and root planing group vs. the saline group (P = 0.02). Reduction in visible dental plaque, which ranged from 38% to 62%, showed no significant differences among treatment groups. CONCLUSIONS The addition of subgingival PVP-iodine irrigation to conventional mechanical therapy may be a cost-effective means of reducing total counts of periodontal pathogens and helping control periodontal disease. However, subgingival irrigation with PVP-iodine without concomitant mechanical debridement might not improve microbiological and clinical variables in comparison with saline irrigation, at least not in sites with radiographic evidence of subgingival calculus.