The aim of the present study was to evaluate the clinical outcome following application of an enamel matrix derivative in degree II mandibular furcation involvements. Ten patients with chronic periodontitis, presenting a total of eight buccal and eight lingual degree II furcation involvements, were included in the study. The following clinical parameters were evaluated prior to treatment and after 6, 12, and 36 months: probing attachment level in horizontal direction in the buccal and/or lingual furcation area (PAL-H) and probing attachment level in vertical direction (PALV) at the center of the buccal/lingual furcation area. The postoperative healing phase was uneventful in all cases, and no complications were observed throughout the entire study period. At 6 months, the mean PAL-H of the buccal defects was reduced from 4.0 ± 1.3 mm to 2.6 ± 1.4 mm, and the mean PAL-V was reduced from 5.2 ± 2.0 mm to 4.0 ± 1.6 mm. At the lingual defects, the mean PAL-H was reduced from 3.6 ± 1.3 mm to 3.1 ± 1.1 mm, and the mean PAL-V was reduced from 5.6 ± 2.0 mm to 4.3 ± 1.8 mm. At 12 and 36 months, clinical parameters remained similar, without any further clinical improvement. These results suggest that the treatment of degree II mandibular furcation involvements with enamel matrix derivative might lead to clinical improvement. However, controlled clinical trials and histologic studies are needed to examine the clinical significance of these results and the characteristics of healing following application of enamel matrix derivative.