Purpose: The objective of this study was to evaluate the efficacy of a zinc-substituted nanostructured monetite-based scaffold (Sil-Oss®) in the treatment of periodontal intra- bony osseous defects. Methods: Thirty subjects participated in this study. Two sites in each subject were randomly assigned into each of the following experimental groups: Test group - open flap debridement (OFD) with Sil-Oss®; and control group - OFD with hydroxyapatite (HA) bone graft. Recorded clinical parameters included site-specific measures of plaque, probing pocket depth (PPD) and clinical attachment loss (CAL) at baseline, 3, 6 and 9 months. The evaluation of bone fill was performed by using digital subtraction technique and morphometric area analysis using two image processing software. Histological evaluation was done after 7 months by taking bone biopsy samples during crown lengthening procedures. Ten regions of interest (ROIs) per slide were visualized for mineralized tissue volume using an Olympus BX53® microscope at 40X magnification. Results: Sil-Oss® showed a significantly greater bone fill compared to HA at 3 and 6 months. Sil-Oss®-treated defects also showed a marked increase in the percentage of tissue mineralization (25.38% vs 23.73%) compared to HA-treated defects. No significant differences were observed between the two groups for CAL and PPD at 6 months. Conclusion: We conclude from this trial conducted over a period of 9 months that Sil-Oss® has the potential to function as a graft material for periodontal regeneration.