Background: Periodontal regeneration success may be limited by placing bone grafts and membranes in infected sites. The objective of this study was to test the hypothesis that adjunctive subgingival administration of chlorhexidine gelatin bio-resorbable chips enhances bone gain when used in conjunction with guided tissue regeneration. Methods: This was a single center, blinded, 2-arm parallel design study of 44 subjects with one or more sites with probing depth and clinical attachment loss ≥5 mm following initial therapy and radiographic evidence of bone loss. The patients were randomly assigned to receive either chlorhexidine (CHX) chip or sham chip placement one week prior to regenerative therapy that included graft placement and site coverage with guided tissue membranes. Patients also received CHX or sham chip placement, per their randomization, adjunctively to scaling and root planing or maintenance procedures. Periodontal examinations were completed at baseline (8 weeks prior to surgery); 1 week prior to surgery; and at 3, 6, and 9 months postsurgery. The major outcomes for the study were changes in bone height and bone mass as measured from standardized radiographs used for quantitative digital subtraction radiography over the 11-month study period. Results: Subjects receiving sham chip placement gained a mean bone height of 1.49 ± 0.22 mm, while patients receiving the CHX chips gained significantly more bone height (3.54 ± 0.45 mm; P <0.001). Similarly, subjects receiving CHX chips as an adjunct gained significantly more bone mass (5.57 ± 0.69 mg; P <0.001) than the standard therapy (2.59 ± 0.34 mg). Conclusions: These pilot results indicate that locally delivered, controlled-release antimicrobial treatment may improve the amount of bone gain during guided tissue regeneration procedures. These data support the evidence that infection control is an important variable in successful regeneration.