OBJECTIVE: Medicines acceptability is likely to have a significant impact on older people's adherence and, consequently, treatment effectiveness. The objective was to explore the influence of setting on medicines acceptability in older people. METHODS: A multi-centre, prospective, cross-sectional, observational study was conducted in one care home and one elderly care hospital ward in London, UK, involving individuals on ≥1 medicine(s) and aged ≥65 years. Data-driven approach was applied using multiple observer-reported outcomes analysis tool to distinguish between positively and negatively accepted medicines. KEY FINDINGS: 263 observer reports from the care home (n = 97) and hospital ward (n = 166) involving 155 distinct medicinal products were assessed. Collectively, medicines appeared better accepted by patients at the hospital. Differences appeared to be driven by variations in solid oral dosage form (SODF) acceptability. Patients with dysphagia poorly accepted medicines in both settings, as expected. SODFs were unexpectedly better accepted in the hospital than in the care home in patients without dysphagia. CONCLUSIONS: Medicines acceptability was affected by patient's characteristics, dosage form type and setting. Changes in care practices between care home and hospital may affect medicine administration and lead to variations in the ability and willingness of patients and carers to use the product as intended.