Human histologic evidence of periodontal regeneration following treatment of intrabony defects with enamel matrix derivative has yielded inconsistent results in recent case reports. A 46-year-old woman presenting one deep intrabony defect at the distal root of a mandibular first molar scheduled for extraction was selected for enamel matrix derivative therapy. During surgery, a notch was placed at the most apical level of calculus on the experimental root. Nine months postsurgery, a block section including the distal root and surrounding periodontal tissues was obtained and processed in a mesiodistal plane. Histologic analysis demonstrated two different patterns of healing along the proximal and furcal surfaces. Regeneration with new cellular cementum, bone, and periodontal ligament with functional fiber orientation was observed on the distal aspect of the root, whereas the furcal surface healed through ankylosis. This report underlines the biologic variability in wound healing following enamel matrix derivative therapy in periodontal intrabony defects and within the same defect. Host-specific intrinsic and/or extrinsic factors accounting for this variability remain to be investigated.