Abstract Background The effects of high dose oncologic radiotherapy on cardiac pacemakers (PMs), at even less than 6MV power, are unpredictable, depending on multiple factors. Normal PM function may be impaired during photon exposure, with potentially life-threatening consequences in PM-dependent patients, and, unlike in magnetic resonance imaging setting, both manufacturer statements and guidelines discourage direct exposure. Purpose To evaluate transient PM malfunctions by direct exposure to doses up to 10 Gy during radiotherapy course, actually not recommended or considered even unsafe, 17 wireless-telemetry-enabled PMs obtained after upgrade or extraction of the system, with sufficient residual battery charge for the purpose of the study (at least 1 year to elective replacement indicator, E.R.I.) were evaluated in a real-time in-vitro session. Methods All PMs underwent baseline interrogation. Single chamber devices were programmed in VVI/40 mode while dual or triple chamber devices were programmed in DDD/40 mode. Rate adaptive function was disabled to avoid the “run-away” phenomenon during exposure. A centering computed tomography was performed to build the corresponding treatment plan and the PMs were blinded randomized to receive either 2, 5 or 10 Gy exposure by a low photon-energy linear accelerator (6MV) in a homemade water phantom (600 MU/min). The effective dose received by the PMs was assessed by an in-vivo dosimetry. During radiotherapy course, the devices were observed in a real-time session using manufacturer specific equipment, and PM function (pacing and sensing, programmed parameters) was recorder by a videocamera in the bunker before (5 minutes), throughout, and after (5 minutes) the entire radiation exposure. Results During radiotherapy course, non of the PMs reported spontaneous changes in parameter settings. 13 PMs (76.5%) recorded non clinically relevant minor transient electromagnetic sensing interferences. No atrial and/or ventricular oversensing nor base-rate-pacing inhibition were observed. Only 4 PMs (23.5%) reported neither transient malfunction nor minor noise, withstanding direct radiation exposure. Transient oversensing-related malfunctions were observed regardless of either 2, 5 or 10 Gy exposure. Conclusions Minor, non clinically relevant electromagnetic sensing interferences were observed in most of the PMs during direct exposure. Nevertheless, to avoid potentially life-threatening PM malfunctions, magnet application on the PM pocket site or reprogramming in the asynchronous mode are still suggested in PM-dependent patients ongoing even low energy radiotherapy exposure. Acknowledgement/Funding None