The new Apexum procedure (Apexum Ltd, Or-Yehuda, Israel) is based on a minimally invasive removal of periapical chronically inflamed tissues through a root canal access. Its goal is to enhance healing kinetics of periapical lesions. This clinical study was conducted to explore the safety and efficacy of this procedure. The Apexum procedure was applied, as a supplementary step, during conventional root canal treatment in 48 teeth with periapical lesions. Safety and efficacy were clinically and radiographically assessed and teeth of the Apexum-treated group were compared with 39 similar teeth treated by the same endodontic procedure with no additional intervention. No adverse events occurred in either the Apexum-treated or conventional treatment groups. Furthermore, healing kinetics was significantly enhanced in the Apexum-treated group (p < 0.005). At 3 and 6 months, 87% and 95% of the lesions in the Apexum-treated group, respectively, presented advanced or complete healing, whereas only 22% and 39% of the lesions in the conventional treatment group presented this degree of healing at 3 and 6 months, respectively.