To analyse the impact of the observed increase in the prevalence in polypharmacy on the development of prescribed drug expenditure (PDE) in a national population during five years. A register-based study of all prescribed drugs and PDE for the entire Swedish population during a 3-month period in 2005 and 2009, respectively. The prevalence of "polypharmacy" and "excessive polypharmacy" was defined as the proportion of patients receiving five or more (PD≥5) and ten or more (PD≥10) prescribed drugs during a 3-month period, respectively. Between 2005 and 2009, the prevalence of polypharmacy increased by 8.3% (from 11.1% to 12.0%), and the prevalence of excessive polypharmacy by 9.9% (from 2.4% to 2.6%). Total PDE increased by 4.8% in real prices. For the group of patients with polypharmacy and excessive polypharmacy, PDE increased by 6.2%, and 7.3%, respectively. A simulation, in which the increase in polypharmacy was neutralised, resulted in no increase in total PDE. The increase in the prevalence of polypharmacy has a substantial impact on the increase in PDE and can explain the entire increase in PDE in Sweden during 2005 to 2009. For clinicians and healthcare stakeholders, it is important to monitor and guidance the further development in multiple medication therapy, so that the cost associated with increasing polypharmacy will not exceed its benefits. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.