Background AU There: Pleaseconfirmthatallheadinglevelsarerepresentedcorrectly is a rising prevalence of multimorbidity, particularly in:older patients, and a need for evidence-based medicines management interventions for this population. The Supporting Prescribing in Older Adults with Multimorbidity in Irish Primary Care (SPPiRE) trial aimed to investigate the effect of a general practitioner (GP)-delivered, individualised medication review in reducing polypharmacy and potentially inappropriate prescriptions (PAU IPs):inPleasenotet community-dwelling older patients with multimorbidity in primary care. Methods and findings We conducted a cluster randomised controlled trial (RCT) set in 51 GP practices throughout the Republic of Ireland. A total of 404 patients, aged =65 years with complex multimorbidity, defined as being prescribed =15 regular medicines, were recruited from April 2017 and followed up until October 2020. Furthermore, 26 intervention GP practices received access to the SPPiRE website where they completed an educational module and used a template for an individualised patient medication review that identified PIP, opportunities for deprescribing, and patient priorities for care. A total of 25 control GP practices delivered usual care. An independent blinded pharmacist assessed primary outcome measures that were the number of medicines and the proportion of patients with any PIP (from a predefined list of 34 indicators based predominantly on the STOPP/START version 2 criteria). We performed an intention-to-treat analysis using multilevel modelling. Recruited participants had substantial disease and treatment burden at baseline with a mean of 17.37 (standard deviation [SD] 3.50) medicines. At 6-month follow-up, both intervention and control groups had reductions in the numbers of medicines with a small but significantly greater reduction in the intervention group (incidence rate ratio [IRR] 0.95, 95% confidence interval [CI]: 0.899 to 0.999, p = 0.045). There was no significant effect on the odds of having at least 1 PIP in the intervention versus control group (odds ratio [OR] 0.39, 95% CI: 0.140 to 1.064, p = 0.066). Adverse events recorded included mortality, emergency department (ED) presentations, and adverse drug withdrawal events (ADWEs), and there was no evidence of harm. Less than 2% of drug withdrawals in the intervention group led to a reported ADWE. Due to the inability to electronically extract data, primary outcomes were measured at just 2 time points, and this is the main limitation of this work. Conclusions The SPPiRE intervention resulted in a small but significant reduction in the number of medicines edforthoseusedthroughoutthetext but no evidence of :aPleaseverifythatallentriesarecorrect clear effect on PIP. This reduction : in significant polypharmacy may have more of an impact at a population rather than individual patient level. Trial registration ISRCTN Registry ISRCTN12752680.