Featured Application: Electrochemical disinfection may revolutionize endodontics and is shown here to not damage host tissue. Boron-doped diamond (BDD) electrodes have been advocated as a potential treatment alternative to the established methods for root canal disinfection. As healing of periapical tissue is important in this context, the associated risk of host tissue damage was to be evaluated. Following in vitro cell culture experiments (HeLa cells), root canal treatment was performed in an animal trial comparing BDD electrode application and the currently used rinsing media with respect to cell viability and host tissue damage. Statistical analyses comparing the size of radiolucency were based on Kruskal-Wallis and Nemenyi’s All Pairs tests (α = 0.05). The direct application of BDD electrodes had a time-dependent effect on cell viability comparable to H₂O₂, NaOCl, and CHX application. In contrast to the chemical treatment, the effect of BDD electrodes was transient. Conventionally treated teeth and teeth additionally treated with BDD electrodes did not significantly differ from each other with respect to the size of the periapical radiolucency as observed radiographically (vertical p = 0.998 and horizontal p = 0.878) and histologically (vertical p = 0.940 and horizontal p = 0.862). While showing greater disinfection efficiency, the application of BDD electrodes for the electrochemical disinfection of root canals does not have a greater risk of host tissue damage compared to the conventional treatment.