Background: Polypharmacy can be defined as using five or more medications simultaneously. "Medication-related problems", an extension of polypharmacy, includes inappropriate prescribing, poor adherence, overdosage, underdosage, inappropriate drug selection, inadequate monitoring, adverse drug effects, and drug interactions. Polypharmacy and the high risk of medication-related problems among older people are associated with adverse health consequences due to drug-drug interactions, drug-disease interactions, and adverse drug effects. This study aims to assess the factors associated with polypharmacy and the high risk of medication-related problems among community-dwelling older people in the Netherlands, Greece, Croatia, Spain, United Kingdom. Method: This longitudinal study used baseline and follow-up data from 1791 participants of the Urban Health Center European project. Polypharmacy and the risk of medication-related problems were evaluated at baseline and follow-up using the Medication Risk Questionnaire. We studied factors in the domains (a) sociodemographic characteristics, (b) lifestyle and nutrition, and (c) health and health care use. Hierarchical logistic regression analyses were used to examine the factors associated with polypharmacy and the high risk of medication-related problems. Results: Mean age was 79.6 years (SD ± 5.6 years); 60.8% were women; 45.2% had polypharmacy, and 41.8% had a high risk of medication-related problems. Women participants had lower odds of polypharmacy (OR = 0.55;95%CI:0.42-0.72) and a high risk of medication-related problems (OR = 0.50; 95%CI:0.39-0.65). Participants with a migration background (OR = 1.67;95%CI:1.08-2.59), overweight (OR = 1.37; 95%CI:1.04-1.79) and obesity (OR = 1.78;95%CI:1.26-2.51) compared to 'normal weight', with lower physical HRQoL (OR = 0.96, 95%CI:0.95-0.98), multi-morbidity (OR = 3.73, 95%CI:2.18-6.37), frailty (OR = 1.69, 95%CI:1.24-2.30), visited outpatient services (OR = 1.77, 95%CI: 1.09-2.88) had higher odds of polypharmacy. The associations with the high risk of medication-related problems were similar. Conclusions: Multiple factors in demography, lifestyle, nutrition, and health care use are associated with polypharmacy and the high risk of medication-related problems. Polypharmacy is a single element that may reflect the number of medications taken. The broader content of medication-related problems should be considered to assess the context of medication use among older people comprehensively. These provide starting points to improve interventions to reduce polypharmacy and high risk of medication-related problems. In the meantime, health professionals can apply these insights to identify subgroups of patients at a high risk of polypharmacy and medication-related problems.