BACKGROUND AND PURPOSE:Polypharmacy is becoming increasingly common owing to the ageing population, which can pose problems for patients and society. We investigated the trends in polypharmacy and underlying drug groups among adults in the Netherlands from 1999 to 2014 stratified by age, and compared these with findings from the United States (US). METHODS:We conducted a repeated cross-sectional study using the Dutch IADB.nl prescription database. All patients aged 20 years and older in the period 1999 to 2014 were included. Polypharmacy was defined as the dispensing of five or more chronic drugs at the pharmacological subgroup level. Chi-square tests were applied to calculate the p-value for trends. Changes in prevalences were compared between the Netherlands and the US. RESULTS:The prevalence of polypharmacy increased from 3.1% to 8.0% (p-value for trend <0.001) over 15 years, and increased in all age groups. The highest rates were observed in patients aged ≥65 years, but the relative increase over time was higher in the younger age groups. Overall, large increases were observed for angiotensin-II inhibitors, statins and proton-pump inhibitors. The relative increase in polypharmacy was larger in the Netherlands than in the US (ratio of polypharmacy prevalence 2.4 versus 1.8). The Netherlands showed larger relative increases for angiotensin-II inhibitors, statins, proton-pump inhibitors, biguanides and smaller relative increases for antidepressants, benzodiazepines and insulins. CONCLUSIONS:Polypharmacy more than doubled from 1999 to 2014, and this increase was not limited to the elderly. The relative increase was larger in the Netherlands compared to the US, which was partly due to larger increases in several guideline-recommended preventive drugs.