The European population of older people with multiple chronic diseases (multimorbidity) is increasing steadily in tandem with the rising population of people aged ≥ 65 years. Older multimorbid people are at high risk of polypharmacy (PP), inappropriate prescribing (IP), adverse drug reactions (ADRs) and adverse drug events (ADEs). PP, IP, ADRs and ADEs in turn cause excessive drug costs and excess healthcare utilization; ADRs and ADEs also cause significant mortality. The current rapid rise in drug expenditure relating mostly to drug use by older people across Europe is not economically sustainable. In tandem with the drug therapy problems, there is underuse of non-drug therapies i.e. physiotherapy, occupational therapy, speech & language therapy, nutritional therapy, psychotherapy in the treatment of chronic diseases in this cohort. Optimal management of drug and non-drug therapy in older multimorbid persons usually requires specialist skill, but most doctors who treat older people do not have specialist training in Geriatric Medicine. To address these challenges, we propose to design and build a software engine (SENATOR) with the capacity to optimize therapy and simultaneously minimize ADRs, IP, PP and excessive cost. SENATOR will evaluate drug indications and contraindications, ADR/ADE risk and detect IP using validated criteria. SENATOR will identify cheapest drug brands to minimize cost. SENATOR will also recommend appropriate symptom-focused drug therapy and avoidance of drugs unlikely to be beneficial in frailer older people with low one year life expectancy. In addition, SENATOR will provide specific advice on appropriate non-drug therapies for individual patients. To test SENATOR’s efficacy, we will perform a multicentre RCT involving 1800 older multimorbid patients hospitalized with acute illness under the care of specialists other than geriatricians, using ADR incidence, medication appropriateness and drug/healthcare costs as the main outcome measures.