This randomized, examiner masked, split mouth study evaluated a new model to test periodontal therapy involving a novel bioerodible copolymer gel containing tetracycline hydrochloride. Responses to the tetracycline gel and untreated control were compared for product tolerance and 3 different measures of effectiveness (drug retention, changes in microbial levels, and clinical status). The test gel was administered by syringe into the periodontal pockets of 18 systemically healthy adult volunteers, each of whom presented with 3 or more sites with 6 mm probing depths. Gingival crevicular fluid samples were used to monitor daily drug levels over 7 days, while clinical responses were assessed at day 30. Overall, the test gel was well-tolerated by all patients. For the 3 effectiveness measures, tetracycline was released throughout the observation period and mean levels exceeded 100 microg/mL over 6 days, statistically significant reductions in selected periodontal pathogens were evident at day 7 but not at day 30, and mean probing depth reductions at test sites were 1.12 mm at 30 days versus 0.36 mm at untreated control sites (P=0.012). The safety profile, longer-term drug retention, antimicrobial activity, and clinical response in this Phase I study suggest that this tetracycline-containing copolymer gel platform may represent a safe and effective bioerodible therapy for periodontitis. The experimental model also shows merit for early phase clinical testing of novel therapeutic agents.