AIM: This study aimed to evaluate the efficacy of the modified minimally invasive surgical technique (M-MIST) combined with a collagen-enriched bovine-derived xenograft (CEBDX) for the treatment of isolated interdental intrabony defects. MATERIALS AND METHODS: This is a randomized controlled trial including 40 isolated interdental intrabony defects in 40 patients. The test group received M-MIST and CEBDX, and the control group received M-MIST alone. Re-evaluations were performed 1 and 2 years after surgery, with probing depth (PD) and clinical attachment level (CAL) measured at the buccal/labial and lingual/palatal sides of the defects as at baseline. Periapical radiographs and CBCT were also performed to evaluate the radiographic bone changes of the defects. RESULTS: Thirty-eight defects were evaluated at the 1- and 2-year follow-ups, and both groups showed statistically significant improvements in PD, CAL and radiographic bone volume. The test group exhibited increased PD reduction (3.95 ± 1.39 mm vs. 2.95 ± 1.51 mm, p = 0.041) and CAL gain (3.58 vs. 2.53 mm on average, p = 0.043) at the buccal side of the defects. No difference was found at the lingual side. A significantly greater radiographic bone volume gain (17.77 ± 11.44 mm CONCLUSIONS: M-MIST was effective both alone and with CEBDX. The addition of CEBDX significantly improved radiographic bone volume gain and PD reduction, and CAL gain at the buccal side of the defects.