The aim of our study was to investigate the occurrence of osteonecrosis of the jaw (ONJ) after implementation of dental preventive measures before starting bisphosphonates (BPs) therapy and during treatment. All consecutive patients with bone lesions eligible for BPs treatment were prospectively evaluated. Before starting BPs, each patient underwent a strict dental preventive program with a specialized odontoiatric team. The odontoiatric evaluation identified patients with oral pathologies or inadequate oral hygiene and provided a dental preventive treatment. From April 2007 to April 2012, 254 patients were enrolled. After excluding patients due to previous BPs treatment, 212 patients with a mean age of 74 years (range 37–95) were included. On average, patients received 9.7 treatment cycles (range 1–48). No ONJ was recorded (0.0 %; 95 % confidence interval CI 0.0–1.4). Comparing this risk with that observed in a previous cohort who did not receive dental prevention (16/186, 8.6 %; 95 % CI 4.2–15.3 %), we observed clear efficacy in preventing ONJ (relative risk reduction: 100 %, 95 % CI 86–100 %, P  < 0.0001). We developed a strict three-step prevention program that is able to decrease ONJ incidence and the need for destructive surgery with permanent sequelae. We demonstrated that ONJ could be effectively prevented. We recommend a mandatory preventive program involving a multidisciplinary team for all patients starting BPs.