The safety and efficacy of a degradable, subgingivally placed drug delivery system containing 2.5 mg chlorhexidine (CHX) were evaluated in a randomized, blinded, multi-center study of 118 patients with moderate periodontitis. A split-mouth design was used to compare the treatment outcomes of scaling and root planing (SRP) alone with the combined use of SRP and the CHX in pockets with probing depths of 5 to 8 mm. The two maxillary quadrants were used for the two treatment arms of the study. Scaling and root planing was performed at baseline only, while the CHX was inserted both at baseline and at 3 months. Clinical and safety measurements including probing depth (PD), clinical attachment level (CAL), and bleeding on probing (BOP) as well as gingivitis, plaque, and staining indices were recorded at baseline, and at 1, 3, and 6 months. The average PD reduction in the CHX-treated sites was significantly greater than in the sites receiving SRP alone at both 3 and 6 months with a mean difference of 0.42 mm (P < or = 0.01) at 6 months. The reduction in CAL at the treated sites was greater than at the SRP sites, although the difference was statistically significant at the 6-month visit only. An analysis of patients with initial probing depths of 7 to 8 mm (n = 56) revealed a significantly greater reduction in PD and CAL in those pockets treated with CHX compared to SRP at both 3 and 6 months. The mean differences between test and control sites at 6 months were 0.71 mm and 0.56 mm PD and CAL respectively.