The primary aims of this two-part prospective study were: 1) to compare the safety and efficacy of beta-tricalcium phosphate (beta-TCP) + 0.3 mg/ml recombinant human platelet-derived growth factor-BB (rhPDGF-BB) with a bioabsorbable collagen wound-healing dressing and a coronally advanced flap (CAF) to a subepithelial connective tissue graft (CTG) in combination with a CAF in subjects with gingival recession defects using a randomized, controlled, split-mouth design; and 2) to compare, through histologic and microcomputed tomography (micro-CT) examination, the periodontal regenerative potential of these two therapies in surgically created gingival recession defects in restoring missing cementum, periodontal ligament (PDL), and supporting alveolar bone. In the randomized controlled trial (RCT), 30 patients with Miller Class II buccal gingival recession, > or = 3 mm deep and > or = 3 mm wide in contralateral quadrants of the same jaw were treated and followed for 6 months. Using a split-mouth design with similar bilateral recession defects, test sites were treated with 0.3 mg/ml rhPDGF-BB + beta-TCP + bioabsorbable collagen wound-healing dressing; contralateral control sites were treated with a CTG, each in combination with a CAF. In the histologic/micro-CT study segment, recession defects were created in six teeth, each requiring extraction for orthodontic therapy. These defects were created with a recession depth > or = 3 mm, the osseous crest 2 to 3 mm apical to the gingival margin, and with 2 to 3 mm of keratinized tissue. The defects were treated with a CTG (control) or rhPDGF-BB + beta-TCP + wound-healing dressing (test), plus CAF. Nine months after surgical correction, en bloc resections were obtained and examined histologically and with micro-CT. In the RCT, test and control treatments demonstrated clinically significant improvements from baseline through month 6. Statistically significant results favoring the CTG were found in recession depth reduction (-2.9 + 0.5 mm, test; -3.3 + 0.6 mm, control; P = 0.009), root coverage (90.8%, test; 98.6%, control; P = 0.013), and -3.9 +/- 0.7 mm, control, -3.3 +/- 1.3 mm, test, recession width reduction (P = 0.035), whereas mid-buccal probing depth (PD) and PD reduction (PDR) reduction favored the test group (1.4 +/- 0.4 mm, test; 1.8 +/- 0.1 mm, control; P < 0.001 PD and -0.0 mm test; +0.4 mm control PDR). For all other parameters, the two treatments were statistically equivalent, including increases in keratinized tissue, esthetic results, and subject satisfaction. In the histologic/micro-CT portion, all four sites treated with rhPDGF-BB + beta-TCP showed evidence of regeneration of cementum, PDL with inserting connective tissue fibers, and supporting alveolar bone, whereas neither CTG-treated site exhibited any signs of periodontal regeneration. CTG and rhPDGF-BB + beta-TCP + wound-healing dressing are effective treatment modalities for clinically correcting gingival recession defects. In addition, the current study demonstrated that regeneration of the periodontium in gingival recession defects was possible through a growth factor-mediated approach.