Polypharmacy increases the risk of side effects and interactions. We quantified the prevalence of major polypharmacy (MPP) in a Danish county with 236,000 inhabitants, invited general practitioners (GPs) to participate in a quality improvement project and discussed the medication of 10-20 MPP patients selected by the participating GPs. This was a prospective registry study of all prescriptions of subsidized drugs in the third quarter of 2005 for all inhabitants living in Roskilde County, Denmark. An audit was performed of the prescriptions of 220 MPP patients selected by the GPs based on a list of each MPP patient's medications. MPP patients constituted 2.1% of the county's population. GPs demonstrated a strong interest in auditing prescriptions. A large share of the patients selected by the GPs was treated with drugs which were no longer indicated, or with drugs with a doubtful indication. MPP compromises the GP's ability to manage medication of individual patients. Systematic audit of the total medication of patients should be introduced.