Objective: This randomized clinical study examined the use of hyaluronic acid to treat infrabony periodontal defects over a period of 24 months. Method and Materials: Forty subjects with a two-wall infrabony defect (probing depth [PD] >= 7 mm; clinical attachment level [CAL] >= 7 mm) were selected. The defects were randomly divided into two groups: sites treated with hyaluronic acid (test group) and those treated with open flap debridement (control group). Results: The 12- and 24-month evaluations were based on clinical and radiographic parameters. The primary outcome variable was CAL. Test defects shows a mean CAL gain of 1.9 ± 1.8 mm, while the control defects yielded a significantly lower gain of 1.1 ± 0.7 mm. PD reduction was also significantly higher in the test group (1.6 ± 1.2 mm) than in the control group (0.8 ± 0.5 mm). Frequency distribution analysis of the study outcomes indicated that hyaluronic acid increased the predictability of clinically significant results (CAL gains >= 2 mm and PD reduction >= 2 mm) in the test group compared with the controls. Conclusions: The treatment of infrabony defects with hyaluronic acid offered an additional benefit in terms of CAL gain, PD reduction, and predictability compared to treatment with open flap debridement. Keywords: hyaluronic acid, infrabony periodontal defect, periodontal disease, periodontal regeneration, randomized clinical trial