Objective: The aim of this 6-month prospective randomized clinical study was to compare the effectiveness of autogenous cortical bone (ACB) and bioactive glass (BG) grafting for the regenerative treatment of intraosseous periodontal defects. Methods: Via a split-mouth design, 15 chronic periodontitis patients (7 men, 8 women; mean age, 43.47 ± 1.45 years) who had probing pocket depths (PPDs) of ≥6 mm following initial periodontal therapy were randomly assigned to receive 2 treatments in contralateral areas of the dentition: ACB grafting and BG grafting. The parameters compared in the patients were preoperative and 6-month postoperative PPDs, clinical attachment levels (CALs), and radiographic alveolar bone heights. Results: Both treatment modalities resulted in significant changes in postoperative measurements when compared to preoperative values (p < 0.01). PPDs were decreased, CALs were increased, and radiographic alveolar bone heights were increased by 5.00 ± 0.28, 4.60 ± 0.21, and 5.80 ± 0.43 mm in patients treated with ACB grafting and 5.13 ± 0.32, 4.67 ± 0.27, and 5.33 ± 0.36 mm in patients treated with BG grafting, respectively. Differences between the treatments were not statistically significant (P<.05). Conclusions: Within the limitations of this study, both ACB and BG grafting led to significant improvements in clinical and radiographic parameters 6 months postoperatively. These results suggest that either an ACB graft, which is completely safe with no associated concerns about disease transmission and immunogenic reactions, or a BG graft, which has an unlimited supply, can be selected for regenerative periodontal treatment.