AIM: To evaluate the clinical and aesthetic outcome of regenerative periodontal therapy (RPT) using minimally invasive surgery and a collagen-enriched bovine-derived xenograft (1); to identify risk factors for failure (clinical attachment level (CAL) gain ≤ 1 mm) and advanced gingival recession (REC) increase (>1 mm) (2). MATERIAL AND METHODS: Ninety-five non-smoking patients, with ≤ 25% full-mouth plaque and bleeding presenting ≥ 6 months after initial periodontal therapy with ≥ 1 isolated inter-dental infrabony defect were recruited. Patients were consecutively treated by the same clinician using minimally invasive surgery and a collagen-enriched bovine-derived xenograft. Clinical, radiographic and aesthetic data were collected before surgery and up to 1 year. Multivariate analyses were used to identify risk factors for failure and advanced REC increase. RESULTS: Eighty-four patients (39 men, 45 women; mean age 53) complied and demonstrated mean probing depth (PD) of 7.8 mm, CAL of 10.0 mm and defect depth of 5.2 mm before surgery. At 1 year, postsurgery mean PD reduction was 3.5 mm (range 0.0-8.0), CAL gain was 3.1 mm (range 0.0-7.0) and radiographic defect fill was 53% (range 0-100). Forty-nine percentage showed ≥ 4 mm CAL gain, whereas 15% were considered failures. Mean inter-dental and midfacial REC increase was 0.3 mm (range-2.0-2.0) and 0.5 mm (range-1.5-2.0) respectively. Midfacial REC increase and contour deterioration contributed most to a small, yet significant reduction in the Pink Esthetic Score from 10.06 to 9.42 (p = 0.002). Risk factors for failure included defects with a non-supportive anatomy (OR: ≥ 10.4), plaque (OR: 14.7) and complication(s) (OR: 12.0). Risk factors for advanced midfacial REC increase included defects with a non-supportive anatomy (OR: 58.8) and a thin-scalloped gingival biotype (OR: 76.9). CONCLUSIONS: RPT using minimally invasive surgery and a collagen-enriched bovine-derived xenograft demonstrated favourable clinical outcome after 1 year, even though soft tissue aesthetics could not be fully preserved. Defects with a non-supporting anatomy may be at risk for failure and advanced midfacial recession.