Background: This study compared clinical and patient‐centered outcomes of sub‐epithelial connective tissue graft (CTG) with and without enamel matrix derivative (EMD) in the treatment of Multiple Class III‐IV Miller periodontal recession defects on lower anterior teeth. Methods: This randomized clinical study evaluated 41 patients over 3 years follow up. 156 teeth were divided into two groups: Test (CTG‐EMD‐ 79 teeth) and Control (CTG only‐ 77 teeth). Clinical Recession (REC), Keratinized Tissue (KT) width, % root coverage, patient centered outcomes were compared between the two groups. Results: At 36 months follow up, patient level analysis showed that REC in the test group reduced significantly (5.71±0.58 mm to 1.57±0.85 mm) compared to the control group (5.94±0.46 mm to 2.51±0.62 mm) (p<0.001), while KT width increase in the test group (1.51±0.26 mm to 4.18±0.34 mm) was significantly greater than the control group (1.65± 0.21 mm to 2.90±0.20 mm) (p<0.001). At 36 months, tooth level analysis (Class III and Class IV groups) found less residual REC and increased KT in the test group compared to the control group (p<.01). Significantly less pain was reported at 2nd, 7th and 14 days follow‐up post‐surgery in the test group (p<0.001). Conclusions: The addition of EMD to CTG results in improved root coverage outcomes and higher amounts of keratinized tissue width 36 months after treatment of Class III‐IV recession on mandibular anterior teeth. The adjunctive use of EMD also resulted in significantly reduced pain 14 days after the surgery.