Abstract Objective To examine the effect of optimising drug treatment on drug related hospital admissions in older adults with multimorbidity and polypharmacy admitted to hospital. Design Cluster randomised controlled trial. Setting 110 clusters of inpatient wards within university based hospitals in four European countries (Switzerland, Netherlands, Belgium, and Republic of Ireland) defined by attending hospital doctors. Participants 2008 older adults (≥70 years) with multimorbidity (≥3 chronic conditions) and polypharmacy (≥5 drugs used long term). Intervention Clinical staff clusters were randomised to usual care or a structured pharmacotherapy optimisation intervention performed at the individual level jointly by a doctor and a pharmacist, with the support of a clinical decision software system deploying the screening tool of older person’s prescriptions and screening tool to alert to the right treatment (STOPP/START) criteria to identify potentially inappropriate prescribing. Main outcome measure Primary outcome was first drug related hospital admission within 12 months. Results 2008 older adults (median nine drugs) were randomised and enrolled in 54 intervention clusters (963 participants) and 56 control clusters (1045 participants) receiving usual care. In the intervention arm, 86.1% of participants (n=789) had inappropriate prescribing, with a mean of 2.75 (SD 2.24) STOPP/START recommendations for each participant. 62.2% (n=491) had ≥1 recommendation successfully implemented at two months, predominantly discontinuation of potentially inappropriate drugs. In the intervention group, 211 participants (21.9%) experienced a first drug related hospital admission compared with 234 (22.4%) in the control group. In the intention-to-treat analysis censored for death as competing event (n=375, 18.7%), the hazard ratio for first drug related hospital admission was 0.95 (95% confidence interval 0.77 to 1.17). In the per protocol analysis, the hazard ratio for a drug related hospital admission was 0.91 (0.69 to 1.19). The hazard ratio for first fall was 0.96 (0.79 to 1.15; 237 v 263 first falls) and for death was 0.90 (0.71 to 1.13; 172 v 203 deaths). Conclusions Inappropriate prescribing was common in older adults with multimorbidity and polypharmacy admitted to hospital and was reduced through an intervention to optimise pharmacotherapy, but without effect on drug related hospital admissions. Additional efforts are needed to identify pharmacotherapy optimisation interventions that reduce inappropriate prescribing and improve patient outcomes. Trial registration ClinicalTrials.gov NCT02986425 .