Funding: The work of Katharina Tabea Jungo was supported by the Swiss National Science Foundation (SNSF) (NFP 407440_167465, PI Prof. Streit) and the work of Zsofia Rozsnyai by the Swiss Society of General Internal Medicine (SGAIM) Foundation (PI Prof. Streit). The SGAIM Foundation reviewed the study protocol but did not give us feedback or help usplan, conduct, interpret results, or write this manuscript. The SNSF had the same role but did not review the study protocol. CM is funded by the National Institute for Health Research (NIHR) Applied Research Collaborations (West Midlands), the NIHR School for Primary Caren Research and an NIHR Research Professorship in General Practice (RP 2014–04-026). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. ER is supported by an NHMRC-ARC Dementia Research Development Fellowship. Background: General practitioners (GPs) should regularly review patients’ medications and, if necessary, deprescribe, as inappropriate polypharmacy may harm patients’ health. However, deprescribing can be challenging for physicians. This study investigates GPs’ deprescribing decisions in 31 countries. Methods: In this case vignette study, GPs were invited to participate in an online survey containing three clinical cases of oldest-old multimorbid patients with potentially inappropriate polypharmacy. Patients differed in terms of dependency in activities of daily living (ADL) and were presented with and without history of cardiovascular disease (CVD). For each case, we asked GPs if they would deprescribe in their usual practice. We calculated proportions of GPs who reported they would deprescribe and performed a multilevel logistic regression to examine the association between history of CVD and level of dependency on GPs’ deprescribing decisions. Results: Of 3,175 invited GPs, 54% responded (N = 1,706). The mean age was 50 years and 60% of respondents were female. Despite differences across GP characteristics, such as age (with older GPs being more likely to take deprescribing decisions), and across countries, overall more than 80% of GPs reported they would deprescribe the dosage of at least one medication in oldest-old patients (> 80 years) with polypharmacy irrespective of history of CVD. The odds of deprescribing was higher in patients with a higher level of dependency in ADL (OR =1.5, 95%CI 1.25 to 1.80) and absence of CVD (OR =3.04, 95%CI 2.58 to 3.57). Interpretation: The majority of GPs in this study were willing to deprescribe one or more medications in oldest-old multimorbid patients with polypharmacy. Willingness was higher in patients with increased dependency in ADL and lower in patients with CVD. publishersversion published