OBJECTIVES: The increased risk of adverse events in patients receiving potentially interacting drugs has long been recognized. The purpose of the present study was to evaluate the change in the risk of receiving potentially interacting drugs during a period covering three decades and to examine the relative risk of actual drug combinations. METHODS: The prescriptions from all individuals (about 8,000) with two or more prescriptions during three periods of 15 months, October to December 1983-1984, 1993-1994 and 2003-2004, were collected from an ongoing cohort study in the county of Jämtland, Sweden. The potential interactions were detected by a computerized system. RESULTS: The relative risk (RR) of receiving potentially interacting drugs increased for type C interactions [RR: 1.177, 95% confidence interval (CI): 1.104-1.256] and decreased for type D interactions (RR: 0.714, 95% CI: 0.587-0.868) from the period 1983-1984 to 2003-2004. Polypharmacy for the participants increased by 61%, from 9.05 filled prescriptions per subject in 1983-1984 to 10.6 in 1993-1994 and 14.6 in 2003-2004. The RR was positively correlated to the pronounced increase in polypharmacy; in addition, an exponential relationship was found for the more severe type D interactions. Few interacting drug combinations were responsible for a large proportion of the risk. CONCLUSION: We conclude that the risk of receiving potentially interacting drugs was strongly correlated to the concomitant use of multiple drugs. The pronounced increase in polypharmacy over time implies a growing reason for prescribers and pharmacists to be aware of drug interactions. Recently established national prescription registers should be evaluated for drug interaction vigilance, both clinically and epidemiologically.