Objective: To compare the long-term clinical outcomes obtained by the combination of platelet-rich plasma (PRP) and a porous hydroxyapatite at the test site with those obtained from the use of a mixture of hydroxyapatite and saline at the control site in the treatment of human intraosseous defects. Method and Materials: Sixty healthy, nonsmoking subjects diagnosed with chronic periodontitis were included in this study. Using a split-mouth design, intraosseous defects were surgically treated with a combination of PRP and a porous hydroxyapatite or a mixture of hydroxyapatite and saline. Clinical measurements and radiographic evaluation were performed at baseline and 1 and 4 years postoperatively. Results: When compared with baseline, the 1-year results showed no significant changes. However, the 4-year results indicated that while both treatment modalities resulted in significant changes in all clinical parameters (probing depth, relative attachment level, gingival recession, and intraosseous defect fill; P .001), the test group exhibited statistically significant changes compared with the control group: probing depth reduction, 5.8 ± 0.49 mm vs 4.0 ± 0.45 mm (P .0001); clinical attachment gain, 5.4 ± 1.2 mm vs 3.1 ± 1.1 mm (P .0001); and defect fill, 3.2 ± 0.8 mm vs 2.1 ± 0.6 mm (P .0001). Conclusion: Treatment with a combination of PRP and hydroxyapatite compared with hydroxyapatite with saline led to a significantly more favorable clinical improvement in intraosseous periodontal defects. Keywords: bone grafts, growth factors, intraosseous defects, periodontal regeneration, platelet concentrate