This prospective, randomized, controlled clinical trial compared the clinical outcomes for a polylactic acid barrier versus a collagen membrane in conjunction with guided tissue regeneration (GTR). Thirty patients with chronic periodontitis and at least one intrabony defect of a minimum 4 mm were enrolled. Following full-mouth scaling, GTR using a collagen membrane or a polylactic acid barrier was performed at one site in each patient. At 1 week before and 6 months after surgery, probing pocket depth (PPD), clinical attachment level (CAL), marginal tissue recession, and bone fill were assessed. A significant reduction in PPD (2.50 ± 1.35 mm for the polylactic acid barrier and 2.60 ± 1.08 mm for the collagen membrane) was obtained, in addition to gains in CAL (2.40 ± 1.17 mm for the polylactic acid barrier and 2.60 ± 1.26 mm for the collagen membrane) and bone fill (0.33 ± 1.89 mm for polylactic acid barrier and 2.57 ± 1.64 mm for collagen membrane), for each group compared to baseline. Significantly, the results from 6 months after surgery showed that there was greater bone fill when the collagen membrane was used compared to the polylactic acid barrier.