Aging and associated morbidities place individuals at higher risk of polypharmacy and drug-drug interactions (DDIs). How polypharmacy and DDIs change with aging is important for public health management. The aim of the study was to assess the 10-year trends in prevalence of polypharmacy and potential DDIs in a population-based sample. Baseline (2003-2006) and follow-up (2014-2016) data were obtained from a sample of 4512 participants (baseline age range = 35-75 y, 55.1% women) from the population of Lausanne, Switzerland. Polypharmacy and polyactive drug use were defined by the regular use of five or more medications and five or more pharmacologically active substances, respectively. Drug-drug interactions were defined according to the criteria of the Geneva University Hospital. The percentage of participants taking at least one drug increased from 56.1% to 79.5% (P < 0.001). Among participants taking drugs, number of medications increased from 2.6 ± 1.9 (mean ± standard deviation) to 3.8 ± 2.9 after 10.9-year follow-up (P < 0.001); the corresponding values for active substances were 2.7 ± 2.0 and 4.0 ± 3.0 (P < 0.001). The prevalence of polypharmacy and polyactive substance use increased from 7.7% to 25.0% and from 8.8% to 27.1%, respectively (P < 0.001). The presence of at least one potential DDI increased from less than 1% to almost one sixth of all participants. In a community-dwelling sample, the prevalence of polypharmacy and polyactive substance use tripled during a 10.9-year follow-up, with an even greater increase in the prevalence of potential DDIs. Increasing rates of polypharmacy and DDIS warns the importance of preventing potential DDIs throughout healthcare system through various interventions. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.