This case cohort study was designed to evaluate the healing response of a minimally invasive surgical technique (MIST) in combination with enamel matrix derivative (EMD) in isolated deep intrabony defects. Forty deep intrabony defects were surgically accessed with the MIST. This technique was designed to limit the flap extent and reflection to reduce surgical trauma and increase flap stability. EMD was applied on the dried root surfaces. Surgery was performed with the aid of an operating microscope and microsurgical instruments. The 1-year clinical attachment level gain was 4.9 ± 1.7 mm. Seventy percent of defects gained >= 4 mm. Clinical attachment level gain was significantly associated with the depth of the three-wall component of the defect, with the intraoperative bleeding tendency of the defect, and with its interaction with the baseline amount of bone loss. Defect morphology and bleeding tendency seem to influence clinical outcomes from the use of MIST in combination with EMD.