A temporary discontinuation (drug holiday) of high-dose antiresorptive (AR) agents has been proposed to reduce the risk of medication-related osteonecrosis of the jaw (MRONJ). The aim of this systematic review was to answer the question: Is high-dose AR drug holiday, at the time of tooth extraction or dentoalveolar surgery, necessary to prevent the development of MRONJ in patients with cancer? This protocol was registered in the PROSPERO database. Medline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched for relevant studies up to and including April 2019. Randomized controlled trials (RCTs), cohort and cross-sectional studies, surveys, and case reports with more than five patients were included. Records were imported into www.covidence.org. Electronic searches were supplemented by manual searches and reference linkage. The Preferred Reporting Items for Systematic Reviews and Meta Analysis (PRISMA) were followed. Although only one study fitted the population, intervention, comparison, outcome (PICO) framework, valuable information on AR drug holiday could be extracted from 14 of 371 reviewed articles. Among these, 3 were prospective and 11 were retrospective studies. These studies described or evaluated high-dose AR drug holidays. In 2 studies, patients were being treated with denosumab, but neither showed that a drug holiday was effective. The remaining 12 studies evaluated bisphosphonate treatment and 2 of these studies found no reason to use AR drug holiday before surgery. Three studies recommended drug holidays, whereas most of the studies recommended assessing each patient separately. The only paper that fitted the PICO approach was a non-randomized, prospective study with a control group. This study concluded that drug holiday was not necessary. Thus, there are no evidence for using drug holiday, but it is also clear that caused by a limited numbers of eligible patients, and a great variation in between these patient, high-level evidence for using AR drug holiday is almost impossible to obtain.